Plan of the lecturePlan of the lecture1. Neoplastic growth. Definition.2. Features of benign and malignant tumors.3. Classification of cancerogens.4. Pathogenesis of tumors.5. Stages of cancerogenesis.6. Characteristic of tumor cells.7. Mechanism of immunological response against tumor cells.8. Treatment of tumors.

Actuality of the lectureActuality of the lecture By the prognoses of Worldwide health protection By the prognoses of Worldwide health protection

organization morbidity and death rate from oncologic organization morbidity and death rate from oncologic diseases in the whole world diseases in the whole world will grow in 2 timeswill grow in 2 times for for period from 1999 year for 2020period from 1999 year for 2020: from 10 to the 20 million : from 10 to the 20 million new cases and from 6 to the 12 million registered deaths. new cases and from 6 to the 12 million registered deaths.

Taking into account that in the developed countries Taking into account that in the developed countries there is a tendency to deceleration of growth of morbidity there is a tendency to deceleration of growth of morbidity and death rate from malignant tumors (due to the and death rate from malignant tumors (due to the prophylaxis and due to the improvement of early prophylaxis and due to the improvement of early diagnostics and treatment), clearly, that a basic increase diagnostics and treatment), clearly, that a basic increase will be at developing countries (countries of former will be at developing countries (countries of former USSR). That is why doctors have to expect serious USSR). That is why doctors have to expect serious increase of morbidity and death rate from oncopathology.increase of morbidity and death rate from oncopathology.

From data of Committee of cancer prophylaxis 90% From data of Committee of cancer prophylaxis 90% tumors are related to influencing of external factors, and tumors are related to influencing of external factors, and 10% - depend on genetic factors. 10% - depend on genetic factors.

Neoplasia – Neoplasia – ““new growth” new growth” & & new new growth is calledgrowth is called a a neoplasmneoplasm.. NeoplasiaNeoplasia is new tissue growth that is: is new tissue growth that is: unregulated, unregulated, irreversible, irreversible, monoclonal.monoclonal. Monoclonal means that the neoplastic cells are derived from a single mother cell.Monoclonal means that the neoplastic cells are derived from a single mother cell.

CancerCancer is an is an overgrowthovergrowth of cells bearing cumulative of cells bearing cumulative genetic injuries genetic injuries that confer growth advantage over the normal cells. that confer growth advantage over the normal cells. [[Nowell’s LawNowell’s Law]]

these features these features distinguish it from distinguish it from

hyperplasia and repairhyperplasia and repair

• Oncology (Greek oncos = tumor) is the study of tumors or neoplasms.

• Cancer is the common term for all malignant tumors.

• Although the ancient origins of this term are somewhat uncertain, it probably derives from the Latin for crab, cancer —presumably because a cancer "adheres to any part that it seizes upon in an obstinate manner like the crab."

Believe it or not, cancer has affected people for several centuries. It is not a new disease.

The word cancer came from the father of medicine, Hippocrates, a Greek physician. He used the Greek words, carcinos and carcinoma to describe tumors, thus calling cancer “karkinos.”

Hippocrates (460-377 BC) coined the term karkinos for cancer of the breast.

The word ‘cancer’ ‘cancer’ means crabcrab, thus reflecting the true character of cancer since ‘it sticks to the part stubbornly like a crabcrab’. He was certainly not the first to discover the disease.

The history of cancer actually begins much earlier.

The History of Cancer, Lisa Fayed, About.com July,2008

• The world's oldest documented case of cancer hails The world's oldest documented case of cancer hails from ancient Egypt, in from ancient Egypt, in 3000 b.c. 3000 b.c.

• The details were recorded on a papyrus, documenting The details were recorded on a papyrus, documenting 8 cases of tumors occurring on the breast. 8 cases of tumors occurring on the breast.

• It was treated by cauterization. It was also recorded It was treated by cauterization. It was also recorded that there was no treatment for the disease, only that there was no treatment for the disease, only palliative treatment.palliative treatment.

• There is evidence that the ancient Egyptians were There is evidence that the ancient Egyptians were able to able to tell the difference between malignant and tell the difference between malignant and benign tumors. benign tumors.

• In ancient Egypt, it was believed cancer was In ancient Egypt, it was believed cancer was caused by the Gods.caused by the Gods. The History of Cancer, Lisa Fayed, About.com July,2008

Ebers Papyrus treatment for cancer: recounting a "tumor against the god Xenus", it recommends "do nothing there against"

http://en.wikipedia.org/wiki/Ancient_Egyptian_medicine

Ancient Egyptian medical instruments

depicted in a Ptolemaic period inscription on the Temple of Kom

Ombo.

TerminologyTerminology

HyperplasiaHyperplasia - - increase in theincrease in the number of cells, number of cells,

HypertrophyHypertrophy - increase in the - increase in the sizes sizes of individual cellsof individual cells. .

AtrophyAtrophy isis an adaptive an adaptive response in which there is a response in which there is a

decrease in the size and decrease in the size and function of cells.function of cells. AnaplasiaAnaplasia - lack of differentiation. - lack of differentiation.

MetaplasiaMetaplasia : : Transformation Transformation of a certainof a certain type of type of differentiated differentiated tissue into tissue into another typeanother type of of differentiated differentiated tissue.tissue.

HeteroplasiaHeteroplasia : : Occurrence of Occurrence of non-neoplasticnon-neoplastic tissue at a tissue at a location where location where it does not it does not normallynormally occur, either in occur, either in a heterotopia a heterotopia or as a resultor as a result of of tissue tissue dissemination.dissemination.

All tumors, All tumors, benignbenign as well as as well as malignantmalignant, have 2 basic components:, have 2 basic components:

““Parenchyma” Parenchyma” comprised by comprised by proliferating tumor cells; proliferating tumor cells; parenchyma parenchyma determines the nature determines the nature and evolution of the and evolution of the tumortumor.

“Supportive stroma” Supportive stroma” composed of fibrous composed of fibrous connective tissueconnective tissueand blood vessels; it and blood vessels; it provides the framework provides the framework on which the on which the parenchymal tumor parenchymal tumor cells grow.cells grow.

NOMENCLATURENOMENCLATURE BenignBenign tumors are designated tumors are designatedby attaching the suffix by attaching the suffix -oma -oma to the cell to the cell of origin. Tumors of of origin. Tumors of mesenchymal mesenchymal cells cells generally follow this rule. generally follow this rule. For exampleFor example, a benign tumor arising , a benign tumor arising from from fibroblastic cellsfibroblastic cells is called is called a a fibromafibroma, , a a cartilaginous tumocartilaginous tumor is r is a a chondromachondroma, a , a tumor of tumor of osteoblasts osteoblasts is an is an osteomaosteoma.. AdenomaAdenoma is the term applied to a is the term applied to a benign epithelial neoplasm that forms benign epithelial neoplasm that forms glandularglandular patterns as well as to patterns as well as to tumors derived from glands but not tumors derived from glands but not necessarily reproducing glandular necessarily reproducing glandular patterns.patterns. Benign epithelialBenign epithelial neoplasms neoplasmsproducing microscopically or producing microscopically or macroscopically macroscopically visible finger-like visible finger-like or or warty projections warty projections from epithelial from epithelial surfaces are referred to as surfaces are referred to as papillomaspapillomas

MalignantMalignant tumours of epithelial tumours of epithelial origin are called origin are called carcinomascarcinomas, while , while malignant malignant mesenchymal mesenchymal tumourstumours are named are named sarcomas (sarcos = sarcomas (sarcos = fleshy)fleshy)For exampleFor example, , fibrosarcoma, fibrosarcoma, liposarcomaliposarcoma, , leiomyosarcomaleiomyosarcoma for for smooth muscle cancersmooth muscle cancer, and , and rhabdomyosarcomarhabdomyosarcoma for a cancer that for a cancer that differentiates toward differentiates toward striated musclestriated muscle). ). However, some cancers are However, some cancers are composed of highly composed of highly undifferentiated undifferentiated cells and are referred to as cells and are referred to as undifferentiated malignant tumours.undifferentiated malignant tumours. Teratomas Teratomas (can be benign)(can be benign), , in in contrast, are made up of a variety of contrast, are made up of a variety of parenchymal cell types parenchymal cell types representative of more than one representative of more than one germ layer, usually all three.germ layer, usually all three.

"Knapsack” tumor: lipoma

Pleural sarcomatosis:Pleural sarcomatosis:metastatic sarcoma of the uterusmetastatic sarcoma of the uterus

CANCER CELLS AND NORMAL CELLS

CANCER CELLSCANCER CELLS NORMAL CELLSNORMAL CELLS

Loss of contact inhibitionLoss of contact inhibition

Increase in growth factor secretionIncrease in growth factor secretion

Increase in oncogene expressionIncrease in oncogene expression

Loss of tumor suppressor genesLoss of tumor suppressor genes

Oncogene expression is rareOncogene expression is rareIntermittent or co-ordinatedIntermittent or co-ordinatedgrowth factor secretiongrowth factor secretionPresence of tumor suppressorPresence of tumor suppressorgenesgenes

NormalNormalcellcell

FewFewmitosesmitoses

FrequentFrequentmitosesmitoses

NucleusNucleus

Blood vesselBlood vessel

AbnormalAbnormalheterogeneous cellsheterogeneous cells

Characteristics of Benign and Malignant Characteristics of Benign and Malignant NeoplasmsNeoplasms

CharacteristicsCharacteristics BenignBenign MalignantMalignantCell Cell

characteristicscharacteristics

Well-differentiated cells that resemble normal cells of the tissue from which the tumor originated

Cells are undifferentiated and often bear little resemblance to the normal cells of the tissue from which they arose

Mode of growthMode of growth

Tumor grows by expansion and does not infiltrate the surrounding tissues; usually encapsulated by a fibrous capsule (exception – uterine leiomyomas do (exception – uterine leiomyomas do not have fibrous tissue capsule)not have fibrous tissue capsule)

Grows at the periphery and sends out processes that infiltrate and destroy the surrounding tissues

Rate of growthRate of growth Rate of growth usually is slowRate of growth is variable and depends on level of differentiation; the more anaplastic the tumor, the more rapid the rate of growth

MetastasisMetastasis Does not spread by metastasis Gains access to the blood and lymph channels and metastasizes to other areas of the body

General effectsGeneral effects

Usually is a localized phenomenon that does not cause generalized effects unless its location interferes with vital functions

Often causes generalized effects such as anemia, weakness, and weight loss

Tissue Tissue destructiondestruction

Usually does not cause tissue damage unless its location interferes with blood flow

Often causes extensive tissue damage as the tumor outgrows its blood supply or encroaches on blood flow to the area; also may produce substances that cause cell damage

Ability to cause Ability to cause deathdeath

Usually does not cause death unless its location interferes with vital functions

Usually causes death unless growth can be controlled

Principal Pathways of Malignancy

1. Proliferation2. Cell-Cycle Progression

3. DNA Repair4. Immortalization

5. Apoptosis6. Angiogenesis

7. Metastasis and Invasion

1)External factors: 1)External factors: tobacco, alcohol, chemicals, radiation, pathogens

2) Internal factors: 2) Internal factors: hormones, immune conditions, inheriled mutations

1. Age > 55 years - more than 75% of cancers. 2. Causes:

3. Blacksa. Greatest risk for

cancerand cancer-relateddeaths of any other

racialgroup or ethnicityb. Applies to almost allcancers exceptmalignant melanoma

4. Hispanics and Asians

Lower incidence rates for all cancers combined thanwhitesb. Exceptions are for cancersassociated with infections – cervix (human

papillomavirus),liver (hepatitis B and C),stomach (Helicobacter pylori)

5. Native Americans• Highest incidence and cancer-related deaths due to kidney cancer than all racial andethnic populations.

Cancer incidenceCancer incidence1. Cancers in children1. Cancers in childrena. a. Second most common cause of death Second most common cause of death in children (accidents most common in children (accidents most common cause)cause)b. b. Acute lymphoblastic leukemiaAcute lymphoblastic leukemia (-33%), (-33%), central nervous system (CNS) tumors (-central nervous system (CNS) tumors (-21%),21%),neuroblastoma (~7%), Wilms' tumor (-neuroblastoma (~7%), Wilms' tumor (-5%).5%).• • These are not common tumors in These are not common tumors in adults.adults.

2. 2. Cancers in men Cancers in men (in decreasing order)(in decreasing order)• • ProstateProstate, lung, colorectal, lung, colorectal

3. 3. Cancers in women Cancers in women (in decreasing order)(in decreasing order)• • BreastBreast, lung, colorectal, lung, colorectal

Cancer Cancer GeographyGeography

1. Worldwide• • Malignant melanoma is Malignant melanoma is increasing at the most increasing at the most

rapidrapidrate of all cancers.rate of all cancers.2. China2. China• • Nasopharyngeal Nasopharyngeal carcinoma secondary to carcinoma secondary to Epstein-Barr virus (EBV)Epstein-Barr virus (EBV)3. Japan3. Japan• • Stomach Stomach adenocarcinomaadenocarcinoma due t0 smoked foodsdue t0 smoked foods4. Southeast Asia4. Southeast Asia• • Hepatocellular carcinomaHepatocellular carcinomadue to hepatitis B virus due to hepatitis B virus

plusplus aflatoxins (produced byaflatoxins (produced byAspergillus) in foodAspergillus) in food

5. Africa5. Africa• • Burkitt's lymphoma due to EBV Burkitt's lymphoma due to EBV

and Kaposi's sarcoma due t0 and Kaposi's sarcoma due t0 human herpes virus 8.human herpes virus 8.

Epidemiology of Endometrial CancerEpidemiology of Endometrial Cancer

Causal Causal TumorigenesisTumorigenesis

CancerCancer is a is a genetic disordergenetic disorder that arises from a that arises from a single body cell (monoclonal disorder). single body cell (monoclonal disorder).

In humansIn humans and other animals, it may be and other animals, it may be triggeredtriggered by by noxious chemicalnoxious chemical, , viralviral, and , and physical agentsphysical agents with with mutagenic effectsmutagenic effects. .

Cells acquire severalCells acquire several characteristics during characteristics during the course of this disease.the course of this disease.

CARCINOGEN CARCINOGEN METABOLISMMETABOLISM

Three Main Categories:Three Main Categories:I. Chemical CarcinogensII. Physical CarcinogensIII. Viral Agents

CarcinogensCarcinogens MutationsMutations CancerCancer

??Environmental Environmental factorsfactors

CARCINOGENSCARCINOGENS

• Occupation related causesOccupation related causes• Lifestyle related causesLifestyle related causes

– TobaccoTobacco– DietDiet– Sexual practicesSexual practices

• Multifactorial causesMultifactorial causes• Chemical carcinogensChemical carcinogens• Ionizing radiationIonizing radiation• Viral carcinogensViral carcinogens

CHEMICAL CARCINOGENESISCHEMICAL CARCINOGENESISDirect-acting CarcinogensDirect-acting Carcinogens

A. A. Alkylating agents• Anti-cancer drugs: cyclophosphamide (transitional cell carcinoma of urinary bladder)(transitional cell carcinoma of urinary bladder), chlorambucil, busulfan, melphalan, nitrosourea etc.• β-propiolactone; • EpoxidesB. Acylating agents:• Acetyl imidazole• Dimethyl carbamyl chloride

PromotersPromoters saccharine & cyclamatessaccharine & cyclamates EstrogenEstrogen ((endometrial carcinoma. Adenocarcinoma of the vagina is seen with increased frequency in adolescent daughters of mothers who had received estrogen therapy during pregnancy). Anabolic steroids (↑ the risk of developing benign and malignant tumors of the liver) Contraceptive hormones Contraceptive hormones ((↑ the risk of developing breast cancer. For long durations are benign tumors of the liver, and a few patients have been reported to have developed hepatocellular carcinoma.

Gregg Valentino

ProcarcinogensProcarcinogens1. Polyclic, 1. Polyclic, aromatic hydrocarbons (in tobacco, smoke, fossil fuel, soot, tar, minerals

oil, smoked animal foods, industrial and atmospheric pollutants) (Lung cancer, skin cancer, cancer of upper aerodigestive tract)• Anthracenes (benza-, dibenza-, dimethyl benza-) • Benzapyrene; • Methylcholanthrene 2. 2. Aromatic amines and azo-dyes:• β-naphthylamine; Benzidine (Bladder cancer)• Azo-dyes (e.g. butter yellow, scarlet red) (hepatocellular carcinoma)3. Naturally-occurring products Aflatoxin B1Aflatoxin B1 ((Hepatocellular carcinoma in association with hepatitis B virusHepatocellular carcinoma in association with hepatitis B virus)) Actinomycin D; Mitomycin C; Safrole; Betel nuts Actinomycin D; Mitomycin C; Safrole; Betel nuts 4. Miscellaneous Nitrosamine & AmidesNitrosamine & Amides Asbestos Asbestos ((Bronchogenic carcinoma, pleural mesotheliomaBronchogenic carcinoma, pleural mesothelioma)) Vinyl chloride Vinyl chloride ((Angiosarcoma, liverAngiosarcoma, liver)) Chromium, nickel, other metals Chromium, nickel, other metals ((Bronchogenic carcinomaBronchogenic carcinoma)) Arsenic Arsenic ((Squamous cell carcinoma of skin, lung cancer, liver angiosarcomaSquamous cell carcinoma of skin, lung cancer, liver angiosarcoma))

3,4-benzopyrene3,4-benzopyrene

This lady chews betel nuts the fruit of a palm

Stages:Stages:

InitiationInitiation - primary exposure - primary exposure

PromotionPromotion - transformation - transformation

Progression Progression - Cancer growth- Cancer growth

CancerCancer

InitiationInitiation normal cells are exposed to a carcinogennormal cells are exposed to a carcinogen not enough to cause malignant transformationnot enough to cause malignant transformation requires one round of cell divisionrequires one round of cell division normal cells are exposed to a carcinogennormal cells are exposed to a carcinogen

1. Direct-acting carcinogens1. Direct-acting carcinogens

2. Indirect-acting carcinogens2. Indirect-acting carcinogens

ProcarcinogenProcarcinogen Cytochrome Cytochrome P450P450

Ultimate Ultimate carcinogencarcinogen

PromotionPromotion initiated cells are exposed to promotersinitiated cells are exposed to promoters promoters are not carcinogens !promoters are not carcinogens ! properties of promotersproperties of promoters reversible reversible

dose-dependentdose-dependent time-dependenttime-dependent

1. Radiation1. Radiation1). Ionizing radiation-induced cancers1). Ionizing radiation-induced cancersa. Mechanism:a. Mechanism:• • Hydroxyl free radical injury to DNAHydroxyl free radical injury to DNAb. Examplesb. Examples(1)(1) Acute myelogenous or chronic myelogenousAcute myelogenous or chronic myelogenous leukemia (leukemia ( risk of leukemia in radiologists and risk of leukemia in radiologists and individuals exposed to radiation in nuclear reactors);individuals exposed to radiation in nuclear reactors);(2) Papillary thyroid carcinoma(2) Papillary thyroid carcinoma(3) Lung, breast, and bone cancers(3) Lung, breast, and bone cancers(4) Liver angiosarcoma (4) Liver angiosarcoma (Due to radioactive thorium (Due to radioactive thorium dioxide used to visualize the arterial tree)dioxide used to visualize the arterial tree)2). UV light-induced cancers2). UV light-induced cancersa. Mechanisma. Mechanism• • Formation of pyrimidine dimers, which distort DNAFormation of pyrimidine dimers, which distort DNAb. Basal cell carcinoma, squamous cell carcinoma,b. Basal cell carcinoma, squamous cell carcinoma,malignant melanomamalignant melanoma2. Physical injury2. Physical injury1). Squamous cell carcinoma may develop in third-degree 1). Squamous cell carcinoma may develop in third-degree

burn scars.burn scars.2). Squamous cell carcinoma may develop at the2). Squamous cell carcinoma may develop at the orifices of chronically draining; orifices of chronically draining; sinuses (e.g., chronic osteomyelitis),sinuses (e.g., chronic osteomyelitis),

Physical CarcinogenesisPhysical Carcinogenesis

PRE-IRRADIATIONPRE-IRRADIATION POST-IRRADIATIONPOST-IRRADIATION

ChondrosarcomaChondrosarcoma

Ultraviolet RaysUltraviolet RaysUV-A = 320 - 400 nm

UV-B = 280 - 320 nm

UV-C = 200 - 280 nm

UV-C UV-C filtered by ozone filtered by ozone

UV-BUV-B

Inhibition of cell division Inhibition of cell division inactivation of enzymes inactivation of enzymes

induction of mutations cell induction of mutations cell death at high dosesdeath at high doses

Squamous cell cancer Squamous cell cancer Basal cell cancer Basal cell cancer MelanocarcinomaMelanocarcinoma

Virus MECHANISM ASSOCIATED CANCERRNA Viruses

HCV Produces postnecrotic cirrhosis Hepatocellular carcinomaHepatocellular carcinomaHTLV-1 (human T-cell lympho-tropic virus)

Activates TAX gene, stimulates polyclonal T-cell proliferation, inhibits TP53 suppressor gene

T-cell leukemia and lymphomaT-cell leukemia and lymphoma

DNA VirusesDNA Viruses

EBV (Epstein-Barr virus)

Promotes polyclonal B-cell proliferation, which increases risk for t(8:14) translocation

Burkitt's lymphoma, CNS Burkitt's lymphoma, CNS lymphoma in AIDS, mixed lymphoma in AIDS, mixed cellularity Hodgkin's lymphoma, cellularity Hodgkin's lymphoma, nasopharyngeal carcinomanasopharyngeal carcinoma

HBV (hepatitis B virus)

Activates proto-oncogenes, inactivates TP53 suppressor gene Hepatocellular carcinomaHepatocellular carcinoma

HHV-8 (human herpesvirus)

Acts via cytokines released from HIV and HSV Kaposi's sarcoma in AIDSKaposi's sarcoma in AIDS

HPV types 16and 18, 31, 33(human papillomavirus)

Type 16 (-50% of cancers); E6 gene product inhibits; TP53 suppressor gene Type 18 (-10% of cancers); E7 gene product inhibits; RB suppressor gene

Squamous cell carcinoma of vulva, Squamous cell carcinoma of vulva, vagina, cervix, anus (associated vagina, cervix, anus (associated with anal intercourse), larynx, with anal intercourse), larynx, oropharynxoropharynx

Viral CarcinogenesisViral Carcinogenesis

Viruses Viruses (in brackets) (in brackets)

in human in human tumors.tumors.

Burkitt's lymphomaBurkitt's lymphoma

Viral carcinogenesisViral carcinogenesis

Laryngeal papillomatosisLaryngeal papillomatosis

Oral cancerOral cancerKaposi's sarcoma Kaposi's sarcoma

A, Replication: Step 1. The DNA virus invades the host cell. Step 2. Viral DNA is incorporated into the host nucleus and T-antigen is expressed immediately after infection. Step 3. Replication of viral DNA occurs and other components of virion are formed. The new virions are assembled in the cell nucleus. Step 4. The new virions are released, accompanied by host cell lysis. B, Integration: Steps 1 and 2 are similar as in replication. Step 3. Integration of viral genome into the host cell genome occurs which requires essential presence of functional T-antigen. Step 4. A ‘transformed (neoplastic) cell’ is formed.

Step 1. The RNA virus invades the host cell. The viral envelope fuses with the plasma membrane of the host cell; viral RNA genome as well as reverse transcriptase are released into the cytosol. Step 2. Reverse transcriptase acts as template to synthesise single strand of matching viral DNA which is then copied to form complementary DNA resulting in double-stranded viral DNA (provirus). Step 3. The provirus is integrated into the host cell genome producing ‘transformed host cell.’ Step 4.Integration of the provirus brings about replication of viral components which are then assembled and released by budding.

Lifestyle Risk FactorsLifestyle Risk FactorsTobacco-related:Tobacco-related: Lung cancerLung cancer Pancreatic cancerPancreatic cancer Bladder cancerBladder cancer Renal cancerRenal cancer Cervical cancerCervical cancer

Lung Lung carcinoma carcinoma in situin situ

Penetration of the vena cava: Penetration of the vena cava: renal carcinomarenal carcinoma

Diet-Related Risk FactorsNitratesSaltLow vitamins A, C, ELow consumption of

yellow-green vegetables

Gastric CancerEsophageal

Cancer

Diet-Related Risk Diet-Related Risk FactorsFactors

High fatLow fiberLow calciumHigh fried foods

Colon CancerPancreatic CancerProstate CancerBreast CancerUterine Cancer

Mycotoxins Liver Cancer

Carcinoma of the prostateCarcinoma of the prostate

Sexual Practices Sexual Practices Risk FactorsRisk Factors

Cervical Cancer

Sexual promiscuityMultiple partnersUnsafe SexHuman Papillomavirus

Multifactorial Multifactorial FactorsFactors

Oral Cavity CancerOral Cavity CancerEsophageal CancerEsophageal Cancer

Tobacco + AsbestosTobacco + miningTobacco + uranium +

radium

Respiratory Tract Respiratory Tract CancerCancer

Lung CancerLung Cancer

Tobacco + Alcohol

CHARACTERISTICS OF CANCERCHARACTERISTICS OF CANCER

• ClonalityClonality

• AutonomyAutonomy

• AnaplasiaAnaplasia

• MetastasisMetastasis

CHARACTERISTICS OF CANCERCHARACTERISTICS OF CANCERClonalityClonality

Clonality can be determined by glucose-6-Clonality can be determined by glucose-6-phosphate dehydrogenase (G6PD) enzyme phosphate dehydrogenase (G6PD) enzyme isoforms.isoforms.

1. Multiple isoforms (e.g., G6PD1. Multiple isoforms (e.g., G6PDAA, G6PD, G6PDBB, and , and G6PDG6PDCC) exist; only one isoform is inherited from ) exist; only one isoform is inherited from each parent.each parent.

2. In females, one isoform is randomly 2. In females, one isoform is randomly inactivated in each cell by lyonization (G6PD is inactivated in each cell by lyonization (G6PD is present on the X chromosome).present on the X chromosome).

3. Normal ratio of active isoforms in cells of any 3. Normal ratio of active isoforms in cells of any tissue is 1:1 (e.g., 50% of cells have G6PDtissue is 1:1 (e.g., 50% of cells have G6PDAA, and , and 50% of cells have G6PD50% of cells have G6PDGG).).

4. 1:1 ratio is maintained in hyperplasia, which is 4. 1:1 ratio is maintained in hyperplasia, which is polyclonal (cells are derived from multiple cells).polyclonal (cells are derived from multiple cells).

5. Only one isoform is present in neoplasia, 5. Only one isoform is present in neoplasia, which is monoclonal.which is monoclonal.

6. Clonality can also be determined by androgen 6. Clonality can also be determined by androgen receptor isoforms, which are also present on the receptor isoforms, which are also present on the X chromosome.X chromosome.

• Cancer cells are able to proliferate despite Cancer cells are able to proliferate despite regulatory influences.regulatory influences.

• Unrestricted proliferation results in tumor Unrestricted proliferation results in tumor formation.formation.

• Mechanisms:Mechanisms:– Growth factor secretionGrowth factor secretion– Increased number of cell receptorsIncreased number of cell receptors– Independent activation of key biochemical Independent activation of key biochemical

processprocess• Proliferation depends on the cell cycle.Proliferation depends on the cell cycle.

CHARACTERISTICS OF CANCERCHARACTERISTICS OF CANCERAutonomyAutonomy

A tumor usually is A tumor usually is undetectable until undetectable until it has doubled 30 it has doubled 30 times and times and contains more contains more than 1 billion than 1 billion (10*9) cells. At (10*9) cells. At this point, it is this point, it is approximately 1 approximately 1 cm in size. cm in size.

After 35 After 35 doublings,doublings,

the mass contains the mass contains more than 1 more than 1 trillion (10*12) trillion (10*12) cells, which is a cells, which is a sufficient number sufficient number to kill the host.to kill the host.

The concept of the Hayflick limit was advanced by Leonard Hayflick in 1961, at the The concept of the Hayflick limit was advanced by Leonard Hayflick in 1961, at the Wistar Institute in Philadelphia. Hayflick demonstrated that a population of normal Wistar Institute in Philadelphia. Hayflick demonstrated that a population of normal human fetal cells human fetal cells in a cell culture in a cell culture will divide between 40 and 60 timeswill divide between 40 and 60 times. The . The population will then enter a senescence phase, which refutes the contention by population will then enter a senescence phase, which refutes the contention by Nobel laureate Alexis CarrelNobel laureate Alexis Carrel that normal cells are immortal.  that normal cells are immortal.

Hayflick found that Hayflick found that cells go through three phasescells go through three phases:: The The firstfirst is rapid, healthy cell division. is rapid, healthy cell division. In the In the secondsecond phase, mitosis slows. phase, mitosis slows. In the In the thirdthird stage,  stage, senescencesenescence, cells stop dividing entirely. Once a cell reaches the , cells stop dividing entirely. Once a cell reaches the

end of its life span, it undergoes a programmed cellular death called end of its life span, it undergoes a programmed cellular death called apoptosisapoptosis.. Each Each mitosismitosis slightly shortens each of the  slightly shortens each of the telomerestelomeres on the DNA of the cells. on the DNA of the cells. Telomere shortening in humans eventually makes cell division impossible, and this Telomere shortening in humans eventually makes cell division impossible, and this

aging of the cell population appears to correlate with the overall physical aging of aging of the cell population appears to correlate with the overall physical aging of the human body. the human body.

This mechanism also appears to This mechanism also appears to prevent genomic instabilityprevent genomic instability. . Telomere shortening Telomere shortening may also may also prevent the development of cancerprevent the development of cancer in human aged  in human aged

cells by limiting the number of cell divisions. cells by limiting the number of cell divisions. However, However, shortened telomeres shortened telomeres impair immune functionimpair immune function that that might also increase might also increase

cancer susceptibilitycancer susceptibility..

The Hayflick limit is the number of times a normal human cell population will divide until cell division stops.

I) I) Epidermal growth factor (EGF)Epidermal growth factor (EGF)II) II) Fibroblast growth factor (FGF)Fibroblast growth factor (FGF)III) III) Platelet-derived growth factor (PDGF)Platelet-derived growth factor (PDGF)IV) IV) Colony stimulating factor (CSF)Colony stimulating factor (CSF)V) V) Transforming growth factors-β (TGF-β)Transforming growth factors-β (TGF-β)VI) VI) Interleukins (IL)Interleukins (IL)VII) VII) Vascular endothelial growth factor Vascular endothelial growth factor (VEGF)(VEGF)

1) 1) Activation of growth-promoting oncogenes Activation of growth-promoting oncogenes causing causing transformation of cell (mutant transformation of cell (mutant form of normal protooncogene in cancer is termed form of normal protooncogene in cancer is termed oncogene). Many of these cancer oncogene). Many of these cancer associated genes, oncogenes, were first discovered in associated genes, oncogenes, were first discovered in viruses, and hence named as viruses, and hence named as v-oncv-onc. Gene products of oncogenes are . Gene products of oncogenes are called called oncoproteinsoncoproteins. . 2) 2) Inactivation of cancer-suppressor genes Inactivation of cancer-suppressor genes (i.e. inactivation of (i.e. inactivation of anti-oncogenes) anti-oncogenes) permitting the cellular proliferation of transformed cells. Anti-oncogenes are active in permitting the cellular proliferation of transformed cells. Anti-oncogenes are active in recessive form recessive form i.e. they are active only if both alleles are damaged.i.e. they are active only if both alleles are damaged.3) 3) Abnormal apoptosis regulatory genes Abnormal apoptosis regulatory genes which may act as which may act as oncogenes or anti-oncogenes or anti-oncogenes. Accordingly, these genes may be active in dominant or recessive form.oncogenes. Accordingly, these genes may be active in dominant or recessive form.4) 4) Failure of DNA repair genes Failure of DNA repair genes and thus inability to repair the and thus inability to repair the DNA damage resulting DNA damage resulting in mutations.in mutations.

1) 1) Proto-oncogenesProto-oncogenes are growth-promoting genes i.e. they are growth-promoting genes i.e. they encode for cell proliferation encode for cell proliferation pathway.pathway.

2) 2) Anti-oncogenesAnti-oncogenes are growth-inhibiting or growth suppressor are growth-inhibiting or growth suppressor genes.genes.3) 3) Apoptosis regulatory genesApoptosis regulatory genes control the programmed cell control the programmed cell death.death.4) 4) DNA repair genes DNA repair genes are those normal genes which regulate are those normal genes which regulate the repair of DNA damage the repair of DNA damage

that has occurred during mitosis and also control the damage to proto-oncogenes that has occurred during mitosis and also control the damage to proto-oncogenes and antioncogenes.and antioncogenes.

MOLECULAR CARCINOGENESISMOLECULAR CARCINOGENESIS

MutationMutation the molecular hallmark of cancerthe molecular hallmark of cancer

Gene Families in Cancer DevelopmentGene Families in Cancer Development

11 - Oncogenes- Oncogenes

22 - Tumor Suppressor genes- Tumor Suppressor genes

33 - Mutator genes- Mutator genes

+ oncogenes

Oncogenes promote cell proliferation dominant & highly conserved types: viral oncogenes [v-oncs]

cellular oncogenes [c-oncs]

Proto-oncogene “Mutation” Oncogene

Classification of OncogenesClassification of Oncogenes

E. Regulators of the Cell CycleE. Regulators of the Cell Cycle

Components of Components of signal signal transduction transduction pathwayspathways

A. Secreted Growth FactorsA. Secreted Growth Factors

B. Cell Surface ReceptorsB. Cell Surface Receptors

C. Intracellular TransducersC. Intracellular Transducers

D. DNA-binding Nuclear ProteinsD. DNA-binding Nuclear Proteins

c-sis, hstc-sis, hst

erb B, fms, ret, trk, fes, fmserb B, fms, ret, trk, fes, fms

c-src, c-abl, mst, rasc-src, c-abl, mst, ras

myc, jun, fosmyc, jun, fos

bcl, bax, badbcl, bax, bad

PROTPROTOO--ONCOONCOGGENEENE FUNCTIONFUNCTION MUTATIONMUTATION CANCERCANCER

ABLABL Nonreceptor tyrosineNonreceptor tyrosine kinase activitykinase activity

Translocation Translocation tt(9:22(9:22))

Chronic myelogenous Chronic myelogenous leukemialeukemia (chromosome (chromosome 22 is Philadelphia22 is Philadelphia chrchr..))

HER HER ((ERBB2)ERBB2) RecepRecepttor synor syntthesishesis AmplificationAmplificationBreast carcinoma Breast carcinoma (marker of (marker of aggressiveness)aggressiveness)

MYCMYC Nuclear transcriptionNuclear transcriptionTranslocaTranslocattion ion tt(8:14)(8:14)

Burkitt's lymphomaBurkitt's lymphoma

N-MYCN-MYC Nuclear transcriptionNuclear transcription AmplificationAmplification NeuroblastomaNeuroblastoma

RASRASGuanosine Guanosine triphosphatetriphosphate signal signal transductiontransduction

Point mutationPoint mutationLeukemia; lung, colon, Leukemia; lung, colon, pancreaticpancreatic carcinomascarcinomas

RETRET Receptor synthesis PoinPointt mulation mulationMultiple endocrine neoplasia lla/llbsyndromes

SIS’SIS’ Growth factor synthesis OverexpressionOverexpression

Osteogenic sarcoma, astrocytoma

Mechanisms of Oncogene ActivationMechanisms of Oncogene Activation

H-rasGTP

Perpetual cell division

1. Point MutationH-ras [codon 12]

Normal CGC GlyBladder ca CTC Val

2. Gene AmplificationDouble minutes

HSRs

Normal copy Multiple copies

Mechanisms of Oncogene ActivationMechanisms of Oncogene Activation

3. Gene Translocation3. Gene Translocation

Ex. Chronic Myelogenous Leukemia [CML]Ex. Chronic Myelogenous Leukemia [CML]

Mechanisms of Oncogene ActivationMechanisms of Oncogene Activation

4. Viral Gene Integration4. Viral Gene Integration

promoter

Viral promoter

ONCOGENSCategories of oncogenes include growth factors, growth factor receptors, signaltransducers, nuclear regulators, and cell cycle regulators

Mechanisms of activation of protooncogenes to form Mechanisms of activation of protooncogenes to form growth promoting oncogenes.growth promoting oncogenes.

Tumor Suppressor Genes Synonym:Synonym: anti-oncogenes Definition:Definition: Collective term for genes whose products physiologically inhibit

cell proliferation, promote cell differentiation, and also suppress certain steps in tumorogenesis and metastasis.

A. Regulate cell growth and, hence, decrease ("suppress")decrease ("suppress") the risk of tumor formation; p53p53 and Rb (retinoblastoma) are classic examples. B. p53p53 regulates progression of the cell cycle from G1 to S phase, 1. In response to DNA damage, p53 slows the cell cycle and upregulates

DNA repair enzymes. 2. If DNA repair is not possible, p53 induces apoptosis. a). p53 upregulates BAX, which disrupts Bcl2. b). Cytochrome c leaks from the mitochondria activating apoptosis, 3. Both copies of the p53 gene must be knocked out for tumor formation

(Knudson two-hit hypothesis). a). Loss is seen in > 50% of cancers. b). Germline mutation results in Li-Fraumeni syndrome (2nd hit is somatic),characterized by the propensity to develop multiple types of carcinomas andsarcomas.

TUMOR SUPPRESSOR GENE TUMOR SUPPRESSOR GENE FAMILY FAMILY Retinoblastoma gene [Retinoblastoma gene [RB1RB1 gene] gene]

rare form of childhood malignancyrare form of childhood malignancy forms: hereditary & sporadicforms: hereditary & sporadic

pRb location: 17p13.1 105-KDa nuclear protein

function: induces DNA repair or apoptosis; inhibits E2F [prevents G1 S transition] inhibited by: phosphorylation, viral oncoproteins [E1A, E1B, HPV E6, E7] mutation: point mutation > deletion results to: loss of function & extended lifespan of p53 Clinical conditions: carcinomas, Li Fraumeni Syndrome

Cell Cycle RegulationCell Cycle Regulation► Process assures that cell accurately duplicates its Process assures that cell accurately duplicates its

contents.contents.► Important checkpointsImportant checkpoints are present at are present at G1 G1 and and G2G2

and are and are regulated by protein kinasesregulated by protein kinases called called cyclinscyclins (cdk).(cdk). ► Checkpoints determine Checkpoints determine

whether the cell whether the cell proceeds to next phase proceeds to next phase of the cycle.of the cycle.

The role of The role of p53 in p53 in maintaining the integrity of maintaining the integrity of the genome. the genome. Activation of normal p53 by Activation of normal p53 by DNA-damaging agents or by DNA-damaging agents or by hypoxia leads to cell-cycle hypoxia leads to cell-cycle arrest in G1 and induction of arrest in G1 and induction of DNA repair, by transcriptional DNA repair, by transcriptional up-regulation of the cyclin-up-regulation of the cyclin-dependent kinase inhibitor dependent kinase inhibitor p21, p21, and the GADD45 genes, and the GADD45 genes, respectively. respectively. Successful repair of DNA Successful repair of DNA allows cells to proceed with the allows cells to proceed with the cell cycle; if DNA repair fails, cell cycle; if DNA repair fails, p53-induced activation of the p53-induced activation of the BAX gene promotes apoptosis. BAX gene promotes apoptosis. In cells with loss or mutations In cells with loss or mutations of p53, DNA damage does not of p53, DNA damage does not induce cell-cycle arrest or DNAinduce cell-cycle arrest or DNArepair, and hence genetically repair, and hence genetically damaged cells proliferate, damaged cells proliferate, giving rise eventually to giving rise eventually to malignant neoplasms.malignant neoplasms.

SOME TUMOR SUPPRESSOR GENES, SOME TUMOR SUPPRESSOR GENES, THEIR FUNCTIONS, AND ASSOCIATED THEIR FUNCTIONS, AND ASSOCIATED

CANCERSCANCERSGENE FUNCTION ASSOCIATED CANCERS

APC (adenomatous polyposis coli)

Prevents nuclear transcriplion (degrades catenin, an activator of nuclear transcription)

Familial polyposis (colorectal carcinoma)

BRCA1/BRCA2BRCA1/BRCA2(breast cancer) Regulates DNA repairRegulates DNA repair Breast, ovary, prosBreast, ovary, prosttate carcinomasate carcinomas

RB (retinoblastoma)

Inhibits G1 to S phaseRelinoblastoma, osteogenic sarcoma, breast carcinoma

TGF-TGF-ββ ((transforming growth factor-β)

Inhibits GInhibits G11 to S phase to S phase PancreaPancreattic and colorectal carcinomasic and colorectal carcinomas

TP53Inhibits G1 to S phase. Repairs DNA, activates BAX gene (initiates apoptosis)

Lung, colon, breast carcinomas. Li-Fraumeni syndrome: breast carcinoma, brain tumors, leukemia, sarcomas

VHLVHL ((Von Von Hippel-Lindau Hippel-Lindau ))

Regulates nuclear transcriptionRegulates nuclear transcription

Von Hippel-Lindau syndrome: cerebellar Von Hippel-Lindau syndrome: cerebellar hemangioblasloma, retinal angioma, renal hemangioblasloma, retinal angioma, renal cell carcinoma (bilateral), cell carcinoma (bilateral), pheochromocytoma (bilateral)pheochromocytoma (bilateral)

WT1 (Wilms' tumor)

Regulates nuclear transcription Wilms' tumor

Antiapoptosis genes; Antiapoptosis genes; BcL2 family of genesBcL2 family of genes Prevent apoptosis in normal cells, but promote apoptosis in Prevent apoptosis in normal cells, but promote apoptosis in

mutated cells whose DNA cannot be repaired (e.g., Bcl2) mutated cells whose DNA cannot be repaired (e.g., Bcl2) a. Protein products prevent cytochrome a. Protein products prevent cytochrome c from leaving mitochondria.c from leaving mitochondria. • • Cytochrome Cytochrome cc in the cytosol activates caspases initiating apoptosis. in the cytosol activates caspases initiating apoptosis. b. Mutation causes increased gene activity (e.g., over expression), which preventsb. Mutation causes increased gene activity (e.g., over expression), which prevents apoptosis; e.g.. apoptosis; e.g.. B-cell follicular lymphoma.B-cell follicular lymphoma. (1) (1) BcL2 gene family BcL2 gene family (chromosome 18) produces gene products that prevent(chromosome 18) produces gene products that prevent mitochondrial leakage of mitochondrial leakage of cytochrome c cytochrome c (signal for apoptosis).(signal for apoptosis). (2) Translocation t(14; 18) causes over expression of the BcL2 protein product.(2) Translocation t(14; 18) causes over expression of the BcL2 protein product. • • Prevents apoptosis of B lymphocytes causing Prevents apoptosis of B lymphocytes causing B-cell follicular lymphomaB-cell follicular lymphoma Apoptosis genesApoptosis genes a. a. Regulate programmed cell death Regulate programmed cell death (ex. BAX apoptosis gene)(ex. BAX apoptosis gene) (1) Activated by a (1) Activated by a TP53 TP53 suppressor gene product if DNA damage is excessivesuppressor gene product if DNA damage is excessive (2) (2) BAX protein BAX protein product inactivates the product inactivates the BcL2 antiapoptosis gene.BcL2 antiapoptosis gene. (3) Mutation inactivating (3) Mutation inactivating TP53 suppressor gene renders the BAX gene inoperative, TP53 suppressor gene renders the BAX gene inoperative,

which prevents apoptosis.which prevents apoptosis.

Anaplasia The third characteristic feature of tumor cells – is

anaplasiaanaplasia, which is cells structural and biochemical organization simplification, coming back to embryonic state.

Neoplastic cells lose a capacity for differentiation and can not form the specific tissue complexes.

Tumor arisesTumor arises from one mutational maternal cell. However such cells differ from their general ancestor by much parameters. These distinctions consearn the cell structure, its organelles, metabolism, specific properties and functions.

Therefore the following kinds of anaplasiakinds of anaplasia are distinguished:

morphological, biochemical, physical and chemical, functional, immunological.

The essence of morphological anaplasiamorphological anaplasia is in appearance of atypic cultural and tissue.

Description of cultural atypic – lays in: cellular polymorphism, nuclear size increase, polynuclear state, nuclear hyperchromatosis, nucleoluses amount increase, mitochondrias changes – quantative size decrease,     crests disappearance Tissue atypism – is sizes and shapes of

tissue structures change, sometimes is the total loss

of morphological tissue signs.

Conjunctival melanoma

Biochemical anaplasiaBiochemical anaplasia – is the tumor cells metabolism peculiarities. – is the tumor cells metabolism peculiarities. Its are arose their genetic system changes, enzymic spectrum of suchIts are arose their genetic system changes, enzymic spectrum of such cells gets changed. All cells get alike by enzymic admission (unification cells gets changed. All cells get alike by enzymic admission (unification of isoenzymic spectrum). of isoenzymic spectrum).

The most typical biochemical feature of neoplasticThe most typical biochemical feature of neoplastic cells cells concern proteins and carbohydrates metabolism. concern proteins and carbohydrates metabolism. Proteins metabolismProteins metabolism peculiarities are: peculiarities are:

synthesis activation of nucleic acids, synthesis activation of nucleic acids, DNA-polymerase inactivation, DNA-polymerase inactivation, increase of proteins  synthesis, increase of proteins  synthesis, decrease of proteins  disintegration.decrease of proteins  disintegration. Carbohydrates  metabolism  and energeticCarbohydrates  metabolism  and energetic of tumor cells  is also of tumor cells  is also

differ of norm. The differ of norm. The main energy sourcesmain energy sources in normal cells are in normal cells are anaerobic and aerobic carbohydrates disintegrationanaerobic and aerobic carbohydrates disintegration,  that is ,  that is glycolysis and Krebs cycle. Neoplastic cell also receives the energy glycolysis and Krebs cycle. Neoplastic cell also receives the energy owing to glycolysis and Krebs cycle. However glycolysis role in tumor owing to glycolysis and Krebs cycle. However glycolysis role in tumor cell is more, than in normal one.cell is more, than in normal one.

The  The  tumor cells energetic supply includetumor cells energetic supply include: : anaerobic glycolysis activation,  anaerobic glycolysis activation,  aerobic glycolysis presence, aerobic glycolysis presence, oppression of Krebs cycle by powerful glycolytical enzymes systemoppression of Krebs cycle by powerful glycolytical enzymes system..

Functional anaplasiaFunctional anaplasia displays in loss or perversion displays in loss or perversion of tumor cells function. of tumor cells function. For example, in For example, in neoplastic thyroid cells  a neoplastic thyroid cells  a surplus amount of surplus amount of hormones thyroxine and hormones thyroxine and triiodothyronine can be triiodothyronine can be synthesized,  thyrotoxicosis synthesized,  thyrotoxicosis arises. arises. In other cases separate functions of tumor cells fall out, for In other cases separate functions of tumor cells fall out, for

example, bilirubin does not get conjugated in hepatocyte. example, bilirubin does not get conjugated in hepatocyte. In very In very malignant neoplastic cellsmalignant neoplastic cells functions are totally lostfunctions are totally lost. .

Sometimes such cells begin doing the functions, which are Sometimes such cells begin doing the functions, which are not specific for them (bronchus cancer synthesizes the not specific for them (bronchus cancer synthesizes the gastrointestinal hormones). gastrointestinal hormones).

Immunological anaplasiaImmunological anaplasia – – is is   change of tumor cell change of tumor cell antigen propertiesantigen properties. In such cells  antigen admission is . In such cells  antigen admission is changed. Several deviation kinds of antigen out of norm changed. Several deviation kinds of antigen out of norm admission are distinguished admission are distinguished antigen simplificationantigen simplification, , antigen divergenceantigen divergence and and antigen reversionantigen reversion. .

Antigen simplificationAntigen simplification – is the general number of – is the general number of neoplastic cells antigens  diminution. For example, the neoplastic cells antigens  diminution. For example, the cells of normal tissue synthesize up to 7 typical antigens, cells of normal tissue synthesize up to 7 typical antigens, while same tissue tumor cells synthesize only 2-3 while same tissue tumor cells synthesize only 2-3 antigens. antigens.

The idea of The idea of antigen divergenceantigen divergence is in the fact of neoplastic is in the fact of neoplastic cells starting to synthesize heterologous antigens. For cells starting to synthesize heterologous antigens. For example, hepatoma (liver tumor) begins synthesizing example, hepatoma (liver tumor) begins synthesizing organospecific spleenic antigens, or other organs organospecific spleenic antigens, or other organs antigens. antigens.

Antigen reversionAntigen reversion means neoplastic embryonic antigens means neoplastic embryonic antigens synthesis. For example, human liver cancer synthesizes a synthesis. For example, human liver cancer synthesizes a special embryonic protein, which is a-fetoprotein.  special embryonic protein, which is a-fetoprotein. 

Invasion and MetastasisInvasion and Metastasis• The defining

characteristic of a malignancy.

• InvasionInvasion: active translocation of neoplastic cells across tissue barriers.

• Critical pathologic point: local invasion and neovascularization. These events may occur before clinical detection.

MetastasisMetastasis• 1. Benign tumors do Benign tumors do not metastasizenot metastasize.• 2. Malignant tumors metastasize.• 3. Pathways of dissemination:• a. Lymphatic spread Lymphatic spread to lymph nodes (usual (usual

mechanism of dissemination of carcinomas)mechanism of dissemination of carcinomas)• b. Hematogenous spreadHematogenous spread: 1) Usual mechanism of dissemination for sarcomas 2) Cells entering the portal vein metastasize to the

liver. 3) Cells entering the vena cava metastasize to the

lungs.

MetastasingMetastasing The final progression stage of any The final progression stage of any

tumor is its transformation into the tumor is its transformation into the malignant neoplasm. The major criteria malignant neoplasm. The major criteria of malignant tumor is its ability to of malignant tumor is its ability to generalisation, that is – to metastasing. generalisation, that is – to metastasing.

Metastasing includes three stageMetastasing includes three stage: : neoplastic invasion into the surrounding neoplastic invasion into the surrounding

tissues, tissues, tumor cells transport with the blood and tumor cells transport with the blood and

lymphatic vessles, lymphatic vessles, their implantation in different organs their implantation in different organs

and tissues. and tissues. Separate cells evacuation out of the Separate cells evacuation out of the

neoplastic node takes place in case of neoplastic node takes place in case of intercellular contacts  relaxation. intercellular contacts  relaxation.

Tumor loses calcium, which must turn Tumor loses calcium, which must turn intercellular spaces cementated in intercellular spaces cementated in malignisation process. Diminished malignisation process. Diminished amount of desmosomes, which create amount of desmosomes, which create the intercellular contacts arises in the intercellular contacts arises in pernicious neoplasms. The amount of pernicious neoplasms. The amount of gangliosides is disranked on the gangliosides is disranked on the cellular surface of malignant tumor.cellular surface of malignant tumor.

ATTRIBUTES OF ATTRIBUTES OF

CANCERCANCER

MetastasisMetastasis

Two basic steps:

Destruction of the BM Attachment to the laminin of distant BM

Genes up-regulated among good metastasizers:EDGF receptorBasic Fibroblast Growth FactorType IV Collagenase-Cathepsin (under-expressed)Cathepsin B (a lamininase)Heparanase

STAGING OF CANCERSTAGING OF CANCER• A. Assessment of size and spread of a cancerA. Assessment of size and spread of a cancer• B. Key prognostic factor; more important B. Key prognostic factor; more important

than gradethan grade• C. Determined after final surgical resection C. Determined after final surgical resection

of the tumorof the tumor• D. Utilizes TNM staging systemD. Utilizes TNM staging system• 1. 1. TT—tumor (size and/or depth of invasion)—tumor (size and/or depth of invasion)• 2. 2. NN—spread to regional lymph nodes; —spread to regional lymph nodes;

secondsecond most important prognostic factor most important prognostic factor• 3. 3. MM—metastasis; single most important —metastasis; single most important

prognostic factorprognostic factor

Metastasis: Metastasis: cervical lymph nodecervical lymph node

Lymph node metastasis

Tissue destruction:Tissue destruction:carcinoma of the maxillary sinuscarcinoma of the maxillary sinus

Cancer "crater”: liver metastases

ANGIOGENESISANGIOGENESIS Formation of new blood vessels from Formation of new blood vessels from

existing vascular bedexisting vascular bed Carried out by endothelial cells (EC) Carried out by endothelial cells (EC)

and extra cellular matrix (ECM)and extra cellular matrix (ECM) Regulated by angiogenic factors Regulated by angiogenic factors

(inducers and inhibitors)(inducers and inhibitors)* * A tumor is unable to grow larger than A tumor is unable to grow larger than

1 mm3 w/o developing a new blood 1 mm3 w/o developing a new blood supplysupply

Components of Components of AngiogenesisAngiogenesis

1)1) ENDOTHELIAL CELLSENDOTHELIAL CELLS FenestratedFenestrated Increased cell adhesion molecules (E-Increased cell adhesion molecules (E-

selectin)selectin) Increased integrins Increased integrins αγβαγβ33 essential for essential for

viability during growthviability during growth Activated ECs release: bFGF PDGFActivated ECs release: bFGF PDGF

IGF-1IGF-1

Components of AngiogenesisComponents of Angiogenesis

2) 2) INDUCERS OF ANGIOGENESISINDUCERS OF ANGIOGENESISVEGF – main inducerVEGF – main inducerTGF- TGF- ββTNF-TNF-αα low concentration - inducer low concentration - inducer

high concentration - inhibitorhigh concentration - inhibitorPDGF/thymidine phosphorylasePDGF/thymidine phosphorylaseTGF-TGF-ααEGFEGFIL-8IL-8

Components of AngiogenesisComponents of Angiogenesis3) CELL ADHESION MOLECULES (CAM)3) CELL ADHESION MOLECULES (CAM) Mediate cell-cell adhesion processesMediate cell-cell adhesion processes SelectinsSelectins IG Supergene family- ICAM, VCAMIG Supergene family- ICAM, VCAM CadherinsCadherins Integrins- vitronectin receptorIntegrins- vitronectin receptor4) PROTEASES4) PROTEASES Degrade ECM to provide suitable Degrade ECM to provide suitable

environment for EC migration thru adjacent environment for EC migration thru adjacent stroma Ex: Metalloproteinases (MMP)stroma Ex: Metalloproteinases (MMP)

Components of Components of AngiogenesisAngiogenesis

5)5) ANGIOGENESIS INHIBITORSANGIOGENESIS INHIBITORS InterferonInterferon TSP-1TSP-1 AngiostatinAngiostatin EndostatinEndostatin VasostatinVasostatinCLINICAL SIGNIFICANCECLINICAL SIGNIFICANCE::Tumor angiogenesis switch is triggered as a Tumor angiogenesis switch is triggered as a

result of shift in the balance of stimulators to result of shift in the balance of stimulators to inhibitorsinhibitors

Immune system and Immune system and neoplastic growthneoplastic growth

Tumor cells are heterologous for the organism. They synthesizethe proteins, Tumor cells are heterologous for the organism. They synthesizethe proteins, which are not character for normal cells. which are not character for normal cells. Neoplasms product Neoplasms product specific swelling specific swelling antigenantigen. Their specificity is conventional, but it is still sufficient for immune . Their specificity is conventional, but it is still sufficient for immune reaction development. A final result depends on immune attack intensity reaction development. A final result depends on immune attack intensity greatly: that means, if the transformed cell is going to reproduct or not; is the greatly: that means, if the transformed cell is going to reproduct or not; is the tumor going to arise, or not. tumor going to arise, or not.

Neoplasms are observed in people with congenital immunodeficiency 10000 Neoplasms are observed in people with congenital immunodeficiency 10000 times more often, than in persons with normal immune system. The malignant times more often, than in persons with normal immune system. The malignant neoplasms arise in patients, with transplanted organ (for example, kidney) very neoplasms arise in patients, with transplanted organ (for example, kidney) very often. Immunodepressive drugs are being prescribed with the purpose of often. Immunodepressive drugs are being prescribed with the purpose of transplanted organ rejection prophylaxy in such patients. Tumors in are transplanted organ rejection prophylaxy in such patients. Tumors in are observed in such cases 100 times more frequent, than in the rest of population.observed in such cases 100 times more frequent, than in the rest of population.

These facts testify, that the transformed cells underlie the organism immune These facts testify, that the transformed cells underlie the organism immune system supervision. In most people they eliminate in time. A transformed cell system supervision. In most people they eliminate in time. A transformed cell exists, reproducts, and produces the neoplasm in a fact of immune supervision exists, reproducts, and produces the neoplasm in a fact of immune supervision insolvency.insolvency.

Tumor renders an oppressive action upon the organism immune system in its Tumor renders an oppressive action upon the organism immune system in its own way. Immunodepression gets developed. own way. Immunodepression gets developed.

The matters, which render immunodepressive action are produced in neoplastic The matters, which render immunodepressive action are produced in neoplastic cells. Low-molecular metabolites (oligopeptides, unsaturated fatty acids), cells. Low-molecular metabolites (oligopeptides, unsaturated fatty acids), embryonic antigens (embryonic antigens (a-fetoproteina-fetoprotein), glucocorticoids belong to them. ), glucocorticoids belong to them.

Т-suppressors activityТ-suppressors activity in patients with tumors in patients with tumors is increasedis increased. They slow down . They slow down antineoplastic immunityantineoplastic immunity. One more reason of immunodepression in . One more reason of immunodepression in oncologic patients is the disparity between neoplastic growth speed oncologic patients is the disparity between neoplastic growth speed and immune answer development speedand immune answer development speed. Lymphoid cells reproduct slower, . Lymphoid cells reproduct slower, than tumor cells do. Adequate immune answer is late.than tumor cells do. Adequate immune answer is late.

Systemic neoplastic action upon Systemic neoplastic action upon the organismthe organism

Tumor is not locally isolated process. It renders an influence upon the Tumor is not locally isolated process. It renders an influence upon the diverse organism functions. This is concerning the malignant diverse organism functions. This is concerning the malignant neoplasms especially. Their systemic action displays the neoplasms especially. Their systemic action displays the cancer cancer cachexycachexy. There are a few components of its development.. There are a few components of its development.Tumor absorbs the glucose reinforcelyTumor absorbs the glucose reinforcely. . Chronic hypoglycaemiaChronic hypoglycaemia tendency tendency arisesarises. Glycogen disintegrates in liver and muscles . Glycogen disintegrates in liver and muscles reinforcely. reinforcely. Glyconeogenesis gets increasedGlyconeogenesis gets increased. However, this . However, this compensatory mechanism has the negative characteristics. Firstly, compensatory mechanism has the negative characteristics. Firstly, glucocorticoids cause the albumens disintegration of glucocorticoids cause the albumens disintegration of immunocompetence organs (thymus, spleen, lymphoid tissue of other immunocompetence organs (thymus, spleen, lymphoid tissue of other organs). Secondly, of big amount of amino acids in glyconeogenesis organs). Secondly, of big amount of amino acids in glyconeogenesis usage gets the organic albumens synthesis limited. Diverse organs usage gets the organic albumens synthesis limited. Diverse organs dystrophy develops, muscles – first of all. dystrophy develops, muscles – first of all. Neoplastic growth can be described with the intensive synthetic Neoplastic growth can be described with the intensive synthetic processes. Plastic material (amino acids, nucleic acids) is very processes. Plastic material (amino acids, nucleic acids) is very important for this. Neoplasm absorbs these matters not only nutritional, important for this. Neoplasm absorbs these matters not only nutritional, but from other organs also. It is named as nitrogen snare. all of other but from other organs also. It is named as nitrogen snare. all of other tissues are having tissues are having amino acid deficiencyamino acid deficiency. They can not synthesize their . They can not synthesize their own proteins in a necessary volume. This is one more link of own proteins in a necessary volume. This is one more link of cancer cancer cachexy pathogens.cachexy pathogens.

Neoplastic Tumors

Tumor ComplicationsTumor Complications The lesions described below complicate theThe lesions described below complicate the

simple growth of the tumor. The combinationsimple growth of the tumor. The combination of of such lesions with tumor expansion and such lesions with tumor expansion and metastasismetastasis constitute neoplastic disease that constitute neoplastic disease that extendsextends beyond the tumor as such.beyond the tumor as such.

Local ComplicationsLocal Complications Stenosis:Stenosis: Tumors can lead to several Tumors can lead to several

compressioncompression syndromes.syndromes. — — Expansion of the tumor Expansion of the tumor compresses compresses the the

surroundingsurrounding tissue tissue (A(A11)) and causes and causes stenosis instenosis in hollow organshollow organs (A2(A2)), compression of the, compression of the small small bowel by a mesenterial liposarcoma;bowel by a mesenterial liposarcoma; Complications may include difficultiesComplications may include difficulties in in swallowing, impaired micturition,swallowing, impaired micturition, disruption of disruption of intestinal motility, and also increasedintestinal motility, and also increased intracranial intracranial pressurepressure..

— — Infiltration of the tumor can cause Infiltration of the tumor can cause congestioncongestion in a hollow organ. Complications mayin a hollow organ. Complications may include include prestenotic dilation of the duct, stasisprestenotic dilation of the duct, stasis and and congestion of secretions or excretions,congestion of secretions or excretions, and and bacterial infestation of the congestedbacterial infestation of the congested area.area.

A 2

1

Tumor compression (mesenterial liposarcoma)

Budd-Chiari Syndrome

Tumor ComplicationsTumor Complications

— — BleedingBleeding due to erosion of vascular due to erosion of vascular structuresstructures may lead to spitting of blood may lead to spitting of blood fromfrom the lungs or bronchi (the lungs or bronchi (hemoptysishemoptysis), ), vomitingvomiting of blood (hematemesis), of blood (hematemesis), passage of bloodypassage of bloody stools (stools (melenamelena), blood ), blood in the urine (hematuria),in the urine (hematuria), acyclic bleeding acyclic bleeding from the uterus (metrorrhagia),from the uterus (metrorrhagia), and and hemorrhagic effusionshemorrhagic effusions (B).(B).

Hemorrhagic effusion (lung cancer)

B

Circulatory Disruption: Tumor growth that compromises or infiltrates vascular structures produces a variety of lesions.— Obstruction of venous drainage is common and successively leads to varicose changes in the walls of the veins and thrombosis.— Vascular thrombosis may result from vascular stenosis and/or substances produced by the tumor itself that promote coagulation.

Tumor Necrosis Tumor Necrosis (C):(C): occurs as a result of occurs as a result of the interplay of the interplay of several factors. These include:several factors. These include:

— — Thrombotic arterial obstruction;Thrombotic arterial obstruction; — — Vascular compression by the tumor;Vascular compression by the tumor; — — Twisting of the tumor pedicle;Twisting of the tumor pedicle; — — Cytokines (macrophagic TNF-a);Cytokines (macrophagic TNF-a); — — Aggressive tumor therapy.Aggressive tumor therapy.Complications of tumor necrosis:Complications of tumor necrosis: – – Ulceration of the inner or outer body surface may Ulceration of the inner or outer body surface may

occur, primarily in gastrointestinal, skin, and breast occur, primarily in gastrointestinal, skin, and breast cancer cancer (D).(D).

– – Perforation of the tumor necrosis may occur into Perforation of the tumor necrosis may occur into hollow organs or through the surface of the skin hollow organs or through the surface of the skin (E).(E).

– – Fistulas may form that communicate with adjacent Fistulas may form that communicate with adjacent organs.organs.

Disruption of Organ Function: occurs especiallyDisruption of Organ Function: occurs especially in in tumors that not only mechanically altertumors that not only mechanically alter the organ the organ parenchyma and its supporting tissueparenchyma and its supporting tissue but also destroy but also destroy them.them.

Particularly susceptible tissues include:Particularly susceptible tissues include: — — Neurovascular structures;Neurovascular structures; — — Urinary tract,Urinary tract, — — Intestinal tract;Intestinal tract; — — Skeletal system, where bone Skeletal system, where bone tumors can causetumors can cause pathologic pathologic fractures fractures (F).(F).

C

D

E

Perforation of the cheek: cancer of the tongue

F

Bone destruction: Ewing sarcoma

Skin ulceration: breast cancer

Necrosis: uterine sarcoma

Systemic ComplicationsSystemic ComplicationsAdvanced neoplastic disease regularly producesAdvanced neoplastic disease regularly produces four types of four types of

systemic lesions.systemic lesions.

Tumor MetastasesTumor Metastases: occasionally: occasionally occur even in the early occur even in the early phases of neoplastic disease.phases of neoplastic disease.

Cancer CachexiaCancer Cachexia: involves weight loss in: involves weight loss in cancer patients. cancer patients. Causes include:Causes include:

— — Impaired swallowing due to the tumor;Impaired swallowing due to the tumor;— — Impaired digestion due to the tumor;Impaired digestion due to the tumor;— — Generation of TNF-a by macrophages stimulatedGeneration of TNF-a by macrophages stimulated by tumor-by tumor-

associated antigens.associated antigens.— — Generation of leptin (fat-cell hormoneGeneration of leptin (fat-cell hormone)). This results in loss of . This results in loss of

appetite appetite (anorexia),(anorexia), reduced intake of nutrients, decreasedreduced intake of nutrients, decreased body fat, and increased energy consumption.body fat, and increased energy consumption.

Tumor AnemiaTumor Anemia: produces the characteristic: produces the characteristic pale skin of cancer pale skin of cancer patients. It is due to severalpatients. It is due to several factors, including:factors, including:

— — Blood loss due to internal bleeding;Blood loss due to internal bleeding;— — Lack of substances that promote maturationLack of substances that promote maturation of blood cells;of blood cells;— — Autoreactive antibodies against erythrocytes;Autoreactive antibodies against erythrocytes;— — Displacement of bone marrow by tumorousDisplacement of bone marrow by tumorous infiltrates.infiltrates.

Paraneoplastic SyndromesParaneoplastic SyndromesDefinition: Collective term for a group of generalized pathologic manifestations that are not attributable to the local effects of a tumor but are linked to the existence of a tumor and can regress after the tumor has been removed.

Pathogenesis: Often unclear.— Cell destruction occurs due to formation of autoreactive antibodies against tumor antigens and “self” antigens and as a result of apoptosis caused by certain tumor proteins.— Dysfunction results from synthesis of peptides with endocrine and enzymatic effects.

EndocrinopathiesGeneral pathogenesis: Tumors synthesize ectopic hormones of substances similar to hormones.The most important forms are as follows:— Cushing’s syndrome is caused by formation of ACTH and occurs in patients with bronchial cancer.— Flush’s syndrome is caused by formation of serotonin and leads to facial erythema, diarrhea, colic, and bronchospasm. It occurs in patients with bronchial or ileal carcinoid.— Schwartz-Bartter’s syndrome is caused by formation of proteins resembling ADH and leads to hyponatremia. It occurs in patients with small cell bronchogenic carcinoma.— Hypercalcemia syndrome is caused by formation of parathormone-like protein. It occurs in patients with squamous cell bronchogenic carcinoma or renal cell carcinomas.

PARANEOPUSTIC SYNDROMESPARANEOPUSTIC SYNDROMESSYNDROME ASSOCIATED CANCER COMMENT

Acanthosis nigricans Stomach carcinomaStomach carcinoma Black, verrucoid-appearing lesion

Eaton-Lambert syndrome

Small cell carcinoma of Small cell carcinoma of lunglung

Myasthenia gravis-like symptoms(e.g., muscle weakness); antibody directed against calcium channel

Hypertrophic osteoarthropathy Bronchogenic carcinomaBronchogenic carcinoma

Periosteal reaction of distal phalanx (often associated with clubbing of nail)

Nonbacterial thrombotic endocarditis

Mucus-secreting pancreatic Mucus-secreting pancreatic and colorectal carcinomasand colorectal carcinomas

Sterile vegetations on mitral valve

Seborrheic keratosis Stomach carcinomaStomach carcinomaSudden appearance of numerouspigmenled seborrheic keratoses (Lescr-Trdlat sign)

Superficial migratory thrombophlebitis Pancreatic carcinomaPancreatic carcinoma

Release of procoagulants (Trousseau's sign)

Nephrotic syndrome Lung, breast, stomach Lung, breast, stomach carcinomascarcinomas

Diffuse membranous glomerulopathy

DISORDER ASSOCIATED CANCER ECTOPIC HORMONE

Cushing syndrome Small cell carcinoma of lung, medullary carcinoma of thyroid

ACTH (adrenocorticotropic hormone)

Gynecomastia Choriocarcinoma (testis)hCG (human chorionic gonadotropin)

Hypercalcemia

Renal cell carcinoma, primary squamous cell carcinoma of lung, breast carcinoma. Malignant lymphomas (contain 1α-hydroxylase)

PTH-relaled protein (parathyroid hormone)Calcitriol (vilamin D)

Hypocalcemia Medullary carcinoma of thyroid Calcitonin

Hypoglycemia Hepatocellular carcinoma Insulin-like factor

Hyponatremia Small cell carcinoma of lung Antidiuretic hormone

Secondary polycythemia

Renal cell and hepatocellular carcinomas

Erythropoietin

Nerve and Muscle SyndromesNerve and Muscle SyndromesPathogenesis: Nerve cells and/or muscle fibers are destroyed by autoimmune processes and

by tumor-induced apoptosis. The most important forms are as follows:• — Myasthenia gravis occurs in patients with thymus tumors (thymomas).• — Limbic encephalopathy occurs in patients with small cell bronchogenic carcinoma.• — Degeneration of the cerebellar cortex occurs in patients with small cell bronchogenic

carcinoma, breast cancer, or ovarian carcinoma.Vascular and Hematologic ChangesVascular and Hematologic Changes• — Hemolysis: The tumor synthesizes cytotoxic substances and/or autoreactive antibodies,

damaging the bone marrow and leading to hemolytic anemia. This occurs in patients with leukemias or Hodgkin’s

• disease’s lymphoma.• — Erythrocyte proliferation: The tumor synthesizes substances that stimulate erythropoiesis

(erythropoietin), leading to polyglobulism (an overabundance of erythrocytes). This occurs in patients with renal cell carcinoma.

• — Leukocyte proliferation: The tumor synthesizes substances that stimulate myelopoiesis, leading to a leukemoid reaction. This occurs in patients with stomach cancer or large cell bronchogenic carcinoma.

• — Macroscopic coagulopathy: The tumor synthesizes thromboplastic substances that lead to thrombosis. This occurs in patients with pancreatic or adenoid carcinomas.

• — Disseminated intravascular coagulation: The tumor synthesizes thromboplastic and fibrinolytic substances that consume the clotting factors. This occurs in patients with leukemias.

• Note: Coagulopathy is characterized by thromboticNote: Coagulopathy is characterized by thrombotic vascular occlusion (primarily in vascular occlusion (primarily in the lung), whereasthe lung), whereas disseminated intravascular coagulation is characterizeddisseminated intravascular coagulation is characterized by hyalin by hyalin microthrombi (primarily in the microvasculaturemicrothrombi (primarily in the microvasculature of the lung).of the lung).

Dermatologic DisordersDermatologic Disorders — — Acanthosis nigricansAcanthosis nigricans manifests itself as manifests itself as thickening of thickening of

the skin with clearly discerniblethe skin with clearly discernible papillary lines, papillary lines, hyperpigmentation, andhyperpigmentation, and wart-like papillomas.wart-like papillomas. It occurs in It occurs in patients with stomach cancer or squamouspatients with stomach cancer or squamous cell bronchogenic cell bronchogenic carcinoma.carcinoma. (А)(А)

— — Bazex’s syndrome Bazex’s syndrome (paraneoplastic acrokeratosis)(paraneoplastic acrokeratosis) manifests itself as reddish purple plaquesmanifests itself as reddish purple plaques of calcification on of calcification on the hands, feet,the hands, feet, nose, and ears.nose, and ears. It occurs in patients with It occurs in patients with carcinoma of the tonguecarcinoma of the tongue or tonsils.or tonsils. ((BB))

— — Erythema gyratum repens Erythema gyratum repens is a rare skin rashis a rare skin rash resembling resembling zebra stripes that changes daily.zebra stripes that changes daily. It occurs in patients with It occurs in patients with various carcinomas.various carcinomas. ((C, D)C, D)

— — Hypertrichosis lanuginosa Hypertrichosis lanuginosa is a rare manifestationis a rare manifestation involving excessive growth of theinvolving excessive growth of the head and body hair.head and body hair. It It occurs in patients with various carcinomas.occurs in patients with various carcinomas. (Е, (Е, F)F)

А

B

C

D

FE

7 warning signs of cancer7 warning signs of cancer CC change in bowel or bladder habitchange in bowel or bladder habit AA a sore that doesn’t heal a sore that doesn’t heal UU unusual bleeding or dischargeunusual bleeding or discharge TT thickening or lumpthickening or lump II indigestion indigestion OO obvious change in wart or moleobvious change in wart or mole NN nagging cough or hoarseness nagging cough or hoarseness

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