Cell Biology of Cancer

Cancer

Cells that grow in an uncontrolled manner and are able to invade other parts of the body. Caused by changes in genetic information which over-ride normal cell function.

Types of tumors

• Benign tumor

• Malignant tumor

Benign Tumors

Uncontroled growth in a confined area, whch is rarly life threatening (eg, wart)

Malignant Tumor

Capable of invading surrounding tissues and (often) spreading to distant parts of the body

• Blood cancers are NOT tumours, but are malignant

Invasion

Direct migration and penetrating into neighbouring tissues

• Cancer cells. lose need for adhesion, and some make proteases to degrade the ECM.

Metastasis

Travel to distant sites in the body via the bloodstream.

Metastases

Tumors formed at new locations

Invasion by tumor cells (steps)

1) Cancer cells invade surrounding tissues and vessels

2) Cancer cells are transported by the circulatory system to disant sites

3) Cancer cells reinvade and grow at a new location.

Genetic Changes (mutations)

• Changes in the nucleotide base sequence of a DNA molecule

• Conversion of a photo-oncogene to oncogenes

• Inactivation of tumor suppressor genes

Epigenetic Changes

• Heritable changes in gene expression, with no change in nucleotides

• Caused by heritable chromatin modifications

• Ex: gene silencing by assembly of heterochromatin.

Oncogene

Is a gene (or gene variant) that can trigger or promote the development of cancer. Begin as photo-oncogenes.

Proto-oncogenes

They are encoded by our genome, and their functions are related to cell survival/growth.

Proto-oncogenes can be converted to oncogenes

1) Mutations that confer uncontrolled activity

2) Mutations that increase their expression

Proto-oncogenes can be converted to oncogenes (example)

25-30% of cancers have mutations that lead to Ras signalling becoming ‘constitutively active’ (always ‘on’), even without growth factor stimulation.

Rb and p53

Best known tumour suppressor genes.

Tumour-suppressor genes

Loss or inactivation of tumour-suppressor genes can lead to cancer.

• Normal function: Restrain cell proliferation (breaks)

Inactivation of Rb and p53 in HPV infections

• Human papillomavirus encodes genes that force division of hot cells

• HPV E7 interferes with Rb, allowing the cell to divide

• Aberrant cell growth usually activates p53, but HPV E6 blocks p53 to keep the cell from dying.

• Uncontrolled proliferation of HPV-infected cells can lead to cervical cancer.

p53 gene (inactivated/disrupted)

• It is inactivated by mutation in almost half of cancers.

• This would cause a failure of apoptosis, allowing cells with DNA damage to survive and reproduce.

Li-Fraumeni

A syndrome caused by the loss of function variants of the p53 gene.

• High likelihood of childhood malignancy.

Colon Cancer

• Well-studied exampel to how cancer results from multiple mutations

• Earliest mutations hasten division, lead to benign tumors

• Later mutations lead to genomic instability and cancer.

Progression of cancer (cells)

1) Normal cells

2) Early benign tumor

3) Intermediate benign tumor

4) Late benign tumour

6) Localized cancer

7) Invasion and metastasis

Progression of cancer (Mutation)

1) APC mutation

2) KRAS mutation*

3) SMAD4 mutation

4) p53 mutation*

5) Other mutations, epigenetic changes*

If p53 is absent

Cells with DNA damage evade cell cycle arrest and apoptosis.

Genomic instability arises most commonly from mutations that disrupt p53 function.

Tumor progression (steps)

1) Initiation

2) Promotion

3) Tumour Progression

Proliferation

In cancer cells, they lose control of this stage.

Cancer progression (Darwinian natural selection)

• Genomic instability creates genetic variability

• Cells with enhanced growth and invasive properties will be the most successful.

Cancer (6 shared properties)

• Self-sufficiency in growth signals

• Evading apoptosis

• Sustained angiogenesis

• Limitless replicative potential

• Tissue invasion and metastasis

• Insensitivity to anti-growth signals

Self-sufficiency in growth signals (basics)

‘Accelerator pedal stuck on’

Insensitivity to ant-growth signals (basics)

‘brakes don’t work’

Evading apoposis (basics)

Won’t die when they normally should

Limitless replicative potential (basics)

Cancer cells can divide forever

Sustained angiogenesis (basics)

Force the body to provide a blood supply

Tissue invasion and matastasis (basics)

Migrating and sprading to other organs and tissues

Self-sufficiency in growth (Characteristics)

• Cells do not normally proliferate unless stimulated by a growth factor

• Cancer cells escape this requirement through the action of oncogenes

• 25-30% of all human cancers have mutant Ras proteins that promote division independently of growth factors.

Insensitivity to Antigrowth Signals (characteristics)

• Normal tissues are protected from excess proliferation by growth-inhibititing mechanisms

• Cancer cells evade such anti-growth signals

• Ex: Mutations of RB that make it no longer able to suppress E2F are associated with retinoblastoma

Evasion of Apoptosis (Characteristics)

• Cancer cells evade apoptosis, which normally destroys cells genetic damage.

• This is often brought about by mutations in the gene that encodes p53

Limitless Replicative Potiential (Characterisitcs)

• Telomere maintenance is usually accemplished by activating the genes encoding telomerase

• Cancer cells must maintain telomere length above a critical threshold

• Thus, they become ‘immortalized’, and can then divide indefinitely.

Sustained Angiogenesis (characterisitics)

• A blood supply is needed for tumors to grow beyond a few millimetres: provide oxygen and nutrients to support growth

• Can cells produce signalling molecules that promote the formation of new blood vessels (Angiogenesis).

Angiogenesis

The formation of new blood vessels creates a blood supply.

Tissue Invasion and Metastasis (Characterisitics)

• Decrease the need for cell-cell adhesion

• Increase motility

• Production of proteases that degrade the basal lamina and extracellular matrix