The Hallmarks of Cancer

Karobi Karobi Moitra (Ph.D)Moitra (Ph.D)NCI Frederick , NIHNCI Frederick , NIHCancer Inflammation ProgramCancer Inflammation ProgramHuman Genetics SectionHuman Genetics SectionFrederick MD.Frederick MD.

Acquired Capabilities of Cancer

Cells

1. Self-Sufficiency in growth signals

Normal cells require mitogenic (cell div) growth signals to move from a quiescent (resting) state into an active proliferation state. Cancer cells can generate their owngrowth signals.

Autocrine signaling : Secretion of a substance or growthfactor that acts on a cell that produced it (i.e. IL2 signaling in monocytes )

Paracrine signaling: secretion of a substance or growth that acts on a nearby cell (i.e. neurotransmitter signaling)

Autocrine

How do cancer cells generate their own growth signals ?

Autocrine signaling: a cancer cell can manufacture it’sown autocrine growth factors.

Active transforming growth factor beta blocks proliferation in normal cell, while downregulation of TGF-betain a cancer cell can induce proliferation by upregulation of cyclins and autocrine growth factors(hypothetical example Grimm and Rosen 2006).

Cancer cells can also switch the types of Extracellular matrix receptors (ECM) they express favoring the

ones that transmit growth signals

ECM : extracellular part of tissue that provides structuralsupport to the cells and performs various other functions

Activation of the Ras-raf pathway through integrins(integrins can mediate signals from the ECM to thecell)

Growth signals

MEK - mitogen activatedprotein kinase kinase

ERK -Extracellular signal regulated kinase

GRB2- growth factor receptor bound protein

2. Insensitivity to Antigrowth signals

If cancer cells are to survive they must block anti-growthsignals. Antigrowth signals can block proliferation by a. Forcing a cell out of the cell cycle into G0.b. Inducing a cell to enter post-mitotic differentiated state.

Transcription factors: switch genes on

E2F is a transcription factor which can switch on genesthat can cause cell division. Rb can inactivate E2F.

Loss of pRB tumor suppressor

3. Evading Apoptosis (cell suicide)

Mutations in p53 can derail apoptosis (preventcell suicide)

What happens when there is a ‘mistake’ or mutation in the code?

Mutations in p53 can derail apoptosis

Insulin like Growth Factors (IGFs) trigger pro-survival(anti-apoptotic) pathways

4. Limitless Replicative Potential

Normal cells age by shortening of chromosomes whentheir telomeres degrade

Telomere

Telomerase synthesizes and maintains telomeresin cancer cells

5. Sustained Angiogenesis

Angiogenesis is the growth of new blood vessels

VEGF - Vascular endothelial growth factor and angiogenesis

The VEGF pathway

6. Tissue invasion and metastasis

Cancer cells synthesize collagenase type lV

E- Cadherin

E-cadherin is disregulated in invasion and metastasis

Loss of anchorage dependence

ParallelPathways

OfTumorigenesis

Reference: The Hallmarks of Cancer , Hanahan D and Weinberg R (2000) Cell, 100: 57-70.