Cell Biology- Chapter 20

CANCER

(Chapter 19 not in exam)

Cancer is a disease of dysregulated cell growth

Oncogenesis (cancer formation) requires DNA changes and failures in immune surveillance

in the absence of genetic predisposition, cancer is most often a disease later in life
Transformation of a normal cell to a tumor cell requires multiple failures, and occurrence of all of those failures in a single cell has a low probability

Cancer cells have abnormal genomes

Oncogenic mutations are typically changes to proto-oncogenes and/or tumor suppressors

Gain-of-function mutations in proto-oncogenes are oncogenic

Hallmarks of Cancer (VERY IMPORTANT)

Sustaining proliferative signaling

mitogen-simulated pathways typically have negative feedback.
Ras/MAPK pathway, hydrolysis of GTP by ras converts back to inactive form
inactivating mutation in the RAS-GTPase domain or the Ras-GAP can produce sustained proliferative signaling

Resisting Cell Death

normal cells require continous pro-survival signaling to suppress activation of the intrinsic pathway of apoptosis
the AKT-Tor signaling pathway promotes both cell growth and survival
conversion of membrane PIP2 to PIP3 by PI3 kinase is upstream of Akt signaling
- PIP 3 can be converted back to PIP2 by the enzyme PTEN (negative regulator)
- Inactivating mutation in PTEN allow for prolonged AKT signaling and survival in the absence of extracellular pro-survival signals
- more notes

Evading growth suppressors

progression of the cell cycle can normally be halted in normal cells via regulation of cell cycle proteins
in the figure below, everything that is green promotes progression, red inhibits
Transformed cells can increase expression of factors like cyclins or Myc or decrease expression…more notes

Replicative immortality

normal somatic cells die after a set number of replications due to progressively shortening telomeres
cancer cells can reactivate telomerase and BECOME IMMORTAL

Inducing angiogenesis

the size of a tumor is initially limited by distance of oxygen. Further growth requires the tumor to encourage new vascular growth.
The hypoxia inducible factor (HIF) pathway is activated by low oxygen pressure and drives expression of many genes. most importantly…more notes

Cancer develops in multiple stages

a single oncogenic mutation is usually not sufficient to promote tumor formation, at least two changes are typically necessary to form a tumor (two-hit hypothesis of carcinogenesis)
in the case of colon cancer, loss of both copies of APC allows excessive proliferation of gut cells
Later on, over-activation of Ras and loss of P53 allows polyps to develop into invasive tumors
further mutations can lead to spread of the cancer to other parts of the body (metastasis)

Activating invasion and metastasis

for the most common cancers (breast and prostate) , its not the primary tumor that kills , but its metastasis.
to spread, an epithelial cancer must penetrate the basal lamina and enter the bloodstream
once in the blood, cancer cells can arrest other tissues… more notes

A palpable tumor contains over 1 billion cells!

the steps of metastasis place multiple selection pressures of tumor cells, it can take years to disseminated cells to form detectible metastases.
- more notes

More hallmarks

Avoiding immune destruction

as cancers progress, they can begin to suppress the immune system
Ipilimumab/yervoy, an antibody, can restore immune function and eliminate some tumors.

Cancer subverts signaling, understanding signaling is the key to beating cancer!