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Cellular and molecular basics of cancer

Yuri Volkov, Ph.D., M.D.

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Cell: a structural unit of cancer

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Key features of normal cells

• Controlled growth due to regulated replication (division) and contact inhibition (receptors)

• Progression from basal (stem) cells state into differentiated state with specialised functions

• Ability to form well organised cell populations, (e.g. in the blood), tissues and organs

• Life cycle ends in an orderly and programmed fashion or in apoptosis

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Khavari Nature Reviews Cancer 2006

A, Normal skin tissueB, Basal cell carcinoma (BCC) shows nodular masses of basaloid cells (B) extend down into the dermis, with tumour nodules showing peripheral palisading of nuclei as well as surrounding stromal elements (S) arranged around tumour masses. The black arrow indicates palisading nuclei. C, Squamous cell carcinoma (SCC) shows irregular masses of atypical epidermal keratinocyte tumour masses (T) invading downwards through the basement membrane zone (BMZ) and dermal matrix (D) accompanied by some retained features of tissue polarity and differentiation in upper layers. D, Malignant melanoma displays upward 'pagetoid' extension of melanoma cells into the epidermis (white arrows) combined with invasion of atypical melanocytic cells and clusters of cells (M) into the dermis.

Examples of cancer growth

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Normal haematopoesis

http://www.allthingsstemcell.com/wp-content/uploads/2009/02/hematopoiesis_simple1.png

http://www.healthsystem.virginia.edu/internet/hematology/HessImages/Normal-Peripheral-Blood-50x-website.jpg

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Chronic lymphocytic leukemia (CLL)

http://pathwiki.pbworks.com/f/1146144287/blood-23.png

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What keeps the normal cell

“normal” and what can go wrong?

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Nuclei, DNA, chromosomes and genes

• The nucleus is a compartment responsible for the storage and timely usage of genetic (hereditary) information in eukariotic cells

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• Genes reside within chromosomes (large structures within the nuclei which are composed of DNA molecules and histone proteins)

Nuclei, DNA, chromosomes and genes

http://www.tiricosuave.com/images/chromosome.jpg

http://ec.europa.eu/research/quality-of-life/image/chromosomes.jpg

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• DNA are biological “macromolecules” composed of two chemical strands twisted around each other and forming a "double helix“)

Nuclei, DNA, chromosomes and genes

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• Each DNA strand is constructed from millions of chemical building blocks represented just by four different “bases”: adenine, thymine, cytosine, and guanine (A, T, G, and C), deoxyribose sugars and phosphates.

Nuclei, DNA, chromosomes and genes

http://www.blc.arizona.edu/Molecular_Graphics/DNA_Structure/DNA_12bp_WF.GIF

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• A gene is a segment of DNA (on a specific site on a chromosome) that is responsible for the physical and inheritable characteristics or phenotype of an organism. The sequential order of the bases in any given gene determines the message which is contained in this gene. Genes also specify the structures of proteins and RNA molecules.

Nuclei, DNA, chromosomes and genes

http://www.biochem.arizona.edu/classes/bioc462/462bh2008/462bhonorsprojects/462bhonors2006/quachg/Images/proteinStructure.gif

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Main types of DNA mutations

• Substitution (switch with another base, creating an irregular sequence):

ABCDEFG BACDEFG

• Insertion (insertion of an extra base to the sequence): ABCDEFG ABHCDEFG

• Deletion (loss of one of the bases in the sequence): ABCDEFG ACDEFG

• Frameshift (insertion or deletion of one of the bases, altering the three bases, or codons completely, creating a different sequence):

ABC DEF GHI BCD EFG HI

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Causes of mutations• Hereditary mutations: contribute to 5-10% of all

cancers• Acquired (sporadic, somatic) DNA mutations:

cause of most cancers • Acquired mutations can happen due to a particular

lifestyle (smoking), dietary factors, environment (e.g. radiation) or toxins

• There are ~ 25,000 genes per cell (the chances are quite high)

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Lung Cancer

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Normal cell cycle and its phases

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Cancer and the cell cycle

• Cells must replicate exactly chromosomal DNA• DNA duplication occurs in S (synthesis) phase• Cell division proceeds in M phase• “Gap” phases are G1 and G2

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The concept of the “cell cycle check points”

• Multiple errors can occur over the entire cell cycle

• Errors must be controlled• Elaborate machinery of

cyclin proteins acting as regulatory units for cyclin dependent kinases (CDKs) is involved in the process

• Genetic errors in controlling cell cycle machinery may be crucial for cancer development

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DNA mutations and cancer

• Mutations are abnormal changes in the DNA sequence affecting one or several genes

• As a result, the synthesis of a certain protein by the cell may be stopped, the produced protein could malfunction or have structural or folding defects. Some proteins may be overproduced or undesired ones will be switched on

• DNA mutations can happen in anyone’s life. However, typically they are either repaired by the internal cell molecular mechanisms, or the cell goes into programmed death pathway (apoptosis)

• If the mutation is not fixed on time, it can lead to cancer

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Oncogenes and tumour suppressor genes• Some genes can contribute to the development of on inherited cancers

(oncogenes)• Most oncogenes appear as a result of mutations of normal genes

called proto-oncogenes. When a proto-oncogene transforms into an oncogene, it can become permanently turned on or activated. Resulting uncontrolled cell growth can lead to cancer

• Inherited mutations of proto-oncogenes: RET gene mutation multiple endocrine neoplasia type 2 (medullary

cancer of the thyroid and other cancers, e.g. pheochromocytoma and nerve tumors)

KIT mutation hereditary gastrointestinal stromal tumors (GIST)MET mutation papillary renal cancer

• Acquired mutations of proto-oncogenes: For example, a chromosome rearrangement leads to formation of the gene called

BCR-ABL mutation chronic myeloid leukemia (CML)KIT mutation most cases of (GIST).

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• A number of genes protect cells from turning into malignant cells (tumour suppressor genes). When they are mutated (inactivated) , cells can start uncontrolled growth leading to cancer

• Tumor suppressor genes are the normal genes dealing with control of cell division, DNA repair or apoptosis (when a cell has DNA damage beyond repair). For example, p53 induces transcription of p21 protein, which forms complexes with G1/S and S cyclin-dependent kinases (CDK), locking them in the “off position” and preventing further cell cycle progression. Cells with mutated DNA encoding p53 continue to grow and divide

• Inherited abnormalities of tumor suppressor genes: deletion in APC gene familial adenomatous polyposis (FAP)

frequently leading to cancer

• Acquired tumor suppressor gene mutations: P53 gene mutations found in over 50% of human cancers (e.g. lung,

colorectal, breast cancer)

Oncogenes and tumour suppressor genes

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P53- “guardian of the genome”

• P53 is activated following a genotoxic insult

• Induced transcription of p21• P21 locks CDK in the off

position• P53 defects can block the

function of the whole chain

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Familial adenomatous polyposis (FAP) and cancer

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Main types of DNA mutations include all of the following, except:

Subst

itutio

n

Del

etio

n

Elim

inat

ion

Tra

nsloca

tion

Fra

mes

hift

6%

0%

6%

50%

38%

A. Substitution

B. Deletion

C. Elimination

D. Translocation

E. Frameshift

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Oncogenes-induced cancer results from:

Inac

tivat

ion o

f pro

to-..

.

Act

ivat

ion o

f pro

to-..

.

Upre

gulat

ion o

f tum

o..

Downre

gulatio

n of t

...

None

of the

abo

ve

0%

73%

7%13%

7%

A. Inactivation of proto-oncogenes

B. Activation of proto-oncogenes

C. Upregulation of tumour suppressor genes

D. Downregulation of tumour suppressor genes

E. None of the above