Biology of Cancer:

What effect does cancer haveon the patient?

Second only to heart disease as a cause of deathCauses much human suffering

Cancer results from damage to DNA which can either be acquired or inherited

All cancers are not the same it is not a single disease

The outcome and prognosis of the cancer ◦ Depends on the cell type and origin◦ The tissue of origin

DISEASE BURDEN

Hereditary Breast Cancer

The type of cancer cell will have a big impact on treatment modalities ◦ ie surgery versus chemotherapy versus no

treatment The progression of the cancer depends on

the cell type in which the cancer arose.

Some cancers are more slow growing and less likely to spread than others

1. Reproduce despite normal constraints that inhibit cell proliferation and clonal expansion -ie a cancer cell loses control over the cell cycle and cell division

Normally a cell only divides following stimulation by growth factors or hormones

2. Cancer cells invade and colonize territories normally reserved for other cells

Characteristics of Cancer cells

Cancer : Unregulated Cell Growth

Autonomous/deregulated cell growth defining feature of all cancers (neoplasms)

Deregulated cell growth not necessarily due to increased cell proliferation - critical balance between

Cancer is caused by the accumulation of genetic alterations that confer a survival advantage to the cancer cell

• Changes may result in:◦ -increased cell growth◦ -resistance to apoptosis◦ -altered tissue invasiveness◦ -angiogenic proliferation

(formation of new blood vessels)◦ -ability to escape immune surveillance

Genetic nature of cancer is reflected in the clonal nature of the cancer cells◦ i.e. daughter cells inherit the properties of the

mother cell • Recognition that cancer is a genetic

disease has lead to intensive effort to characterize genes responsible which has lead to new therapies

CANCER IS CLONAL

The change from a normal cell to a cancer cell is called cell transformation◦ Cancer cells don’t look like normal cells◦ The pathologist uses the change in the

appearance of the cell to diagnose the cancer

Cancer cells show – enlarged nucleus, changes to the cytoskeleton, loss of specialized features

There is a spectrum in the changes in appearance of the cancer cell

With some highly malignant cancers it is impossible to tell the cell of origin

Much data to suggest as a cancer develops there is the accumulation of genetic errors and increasing change in cell appearance

Photographs of cells collected by scraping the surface of the uterinecervix (the Papanicolaou or “Pap Smear” technique).

Appear under the microscope like the tissues they came from◦ Remain localized and do not spread◦ Usually do not cause problems unless they grow

in a confined space ie. the brain

Benign Tumours

Do not resemble the tissue or cell of origin◦ Often have irregular structures, large variable

nucleus, little cytoplasm, evidence of mitosis, little specialized structures

• Invade surrounding tissues

Malignant Tumours

Cancers invade other tissues and spread to other parts of the body – this is called metastasis

• Metastasis can be local or distant

• Spread of cancer may depend on the type of cancer ie some are more likely to spread than others◦ eg. small cell lung cancer usually metastatic at

time of patient presentation

Cancer Metastasis

Metastasis occurs in several stages and can occur via several routes

• Local • Lymphatic • Blood

For cancer cell to metastasize it requires genetic change

• These changes lead to change in the cells function and appearance

• Decreased ability of the cells to adhere to neighbouring cells

• Increased ability of the cancer cells to move

Cancer cells extend into surrounding tissue by degrading extracellular matrix

-ie. secrete proteolytic enzymes- cancer cells migrate into lymphatics and blood vessels

Cancer cells need to be able to provide an adequate blood supply◦ Angiogenesis – development of a new microcirculation

Cancer cells that acquire these characteristics have a growth advantage, will be clonally selected and given a suitable environment will grow and proliferate

The cancer cell acquires growth advantages via mutations to DNA -ie cancer is a genetic disease

• Daughter cells inherit the genetic mutations and therefore inherit the growth advantage

• Cancer cells from an individual cancer tend to look the same - all related as the daughter cells inherit the same abnormalities

Even when a cancer has spread the origin of the cell can usually be traced back to a single cell of origin

• The original cancer cell has a growth advantage – it can grow, divide and invade better than normal cells

The cancer cell has undergone a transformation which gives it a growth advantage

Cancer cells are clonal

Different types of cancer occur as there are many different cell types in specific tissues and organs

• About 85% of all cancers are Carcinomas arising from the skin, and epithelial cells that line the organs - examples include breast cancer, lung cancer, colon cancer

• Sarcomas arise from bone, muscle, blood vessels

• Lymphoma arise from lymphoid cells and leukemias from white cells of the bone marrow

Cancer has both local and distant effects

What effect does cancer have on a patient ?

• Cancer displaces normal adjacent tissue • The function of the tissue deteriorates as

the normal cells are replaced by cancer cells which cannot perform the normal cells specialized function◦ -ie bone marrow – making blood cells.

Leukemias replace normal bone marrow◦ -ie Brain tumours replace normal brain tissue

with a specialized function◦ • Cancer cells are immature and cannot carry

out specialized function

LOCAL EFFECTS - 1

Cancers can block vital passages • The mass of a local or metastasized tumour

may become very large -i.e. colon cancers may grow locally and block the

lumen of the bowel so that it becomes obstructed, even in the absence of distant metastasis

• Tumours may block the normal arterial, venous or lymphatic supply leading to significant symptoms

LOCAL EFFECTS- 2

Cancer cells have a very rapid growth and turnover

• The proliferation of cancers leads to a high metabolic rate

• Cancer cells compete with normal cells for nutrition and blood supply

• Other organs may break down their own proteins to nourish the cancer – patient may lose a lot of weight

Effects of cancer on the patient

Patient may experience weight loss, fatigue, tiredness. When weight loss is massive and dramatic and the patient becomes profoundly wasted – called cachexia

• Occasionally cancers may secrete hormones which will cause distant effects even when the cancer has not spread – so called non metastatic manifestations of cancer

- ie lung cancer secretes cortisol

Cancer spread or metastasis is a common cause of cancer related deaths

• Cancer spread ◦ –distant – via lymphatics lymph nodes, lymphatics and

eventually drain into the venous circulation, lungs, heart, and via circulation to other organs

◦ - via blood stream - circulation –distal organs • Cancer spread may be local – block a vital organ - compress vital local tissues, nerves and blood

vessels and block lymphatics

Specific mechanical factors may regulate where a cancer spreads

• The site of the primary tumour ◦ ie colon or breast or kidney and where the

venous drainage from that organ drains to. • For example the liver is the main site of

spread from colon cancer

Mechanical Factors which regulate metastatic deposition

The actual size of the cancer cell may regulate the retention of the cell in specific organ systems.

• Both the lung and the liver are frequent, serious sites for the spread of cancer. This may relate to the size of the cancer cells (20 micron) versus the site of the capillaries in these organs – 3-8 micron, so the cancer cells get stuck and then adhere and grow in that site

1/10 women will get breast cancer Many men will get prostate cancer Patients with breast and or prostate

cancer frequently get bone metastases (may not relate to having an aggressive tumour)

Bone metastases ◦ – lead to hypercalcaemia◦ - osteolytic lesions (holes in bone )◦ - fractures◦ - osteoporosis

Why do cancers preferentially spread to somesites?

Lytic

Blastic

Bone metastasis is often classified as either a |osteolytic or b | osteoblastic, and one of these effects is

usually predominant. For example

◦ metastases from breast and lung tumours are generally osteolytic, whereas metastases from prostate cancer are generally osteoblastic.

◦ However, most blastic metastases have a resorptive component, and most lytic lesions are accompanied by some attempt at repair or bone formation.

Types of bone metastases

Cancers may spread specifically to bone because the bonematrix or cytokines secreted by the cancer such as PTHRP

enhance cancer growth

Effects – • May cause severe pain • Weaken bone and causes pathological

fractures • Weaken bone and cause deformities –

nerve compression, spinal cord ompression as a result of vertebral body collapse

• Hypercalcaemia

Cancer Spread to Bone

Some cancers may reappear decades after the excision of the primary tumour and there may have been no evidence of cancer for years – cancer dormancy◦ • Seen with cancer of the breast and melanoma

Several studies have suggested cancer dormancy may result from failure of the cancer micrometastasis to develop its own blood vessels – therefore the tumour may survive but not expand.

Cancer Dormancy

The reasons why the tumour may suddenly start to grow years later may relate to its acquisition of an increased blood supply

• Novel therapeutic strategies in anti-angiogenic therapies may stop tumour proliferation in metastasis

Alberts et al. Molecular Biology of the Cell 4th ed • Karp. Cell and Molecular Biology 4th ed • Purveset al. Life 6th and 7th ed • Cancer in Australia 2001. Report by Australian

Institute of Health and Welfare (AIHW) 2004 • Jameson JL. Principles of hormone action. Oxford Textbook of Medicine, 3rd ed. 1996; pp. 1553-1573 • Swartz, M.H. Textbook of Physical Diagnosis.

History and Examination (1989) • Nature Reviews Cancer 2002, 2: 573-580, 584-

590

REFERENCES