Tumor Biology, Syndromes, and Genetic Mutations

I

Self-Sufficiency in Growth Signals

Mitogens are chemicals that trigger cell mitosis. In contrast with healthy cells, cancer cells have a reduced dependence on mitogens and external growth factors for replication.

A

Growth Factors

1.
Tumor cells and stroma produce factors that may influence tumor growth and stimulate cell environment.
2.
Transforming growth factor-beta (TGF-beta) affects angiogenesis, extracellular matrix, and production of cytokines.

B

Alteration of Growth Signaling Pathways

1.
Growth factor receptors may be overexpressed or structurally altered.
2.
Overexpression may allow cells to be stimulated by very low levels of growth factors.
3.
Amplification of human epidermal growth factor receptor 2/neu (HER2/neu) is found in some forms of aggressive breast cancer.

C

Sos/Ras/Raf/Mitogen-Activated Protein Kinase Pathway

1.
This is altered in approximately 25% of human cancers.
2.
K-ras mutations are found in lung, pancreatic, and colon cancers.
3.
The Ras oncogene encodes mutant protein that continuously releases mitogenic signals.

D

Tumor Growth is Dependent on Many Factors

1.
Angiogenesis factors, growth factors, chemokines, cytokines, hormones, enzymes, and cytolytic/cytostatic factors

II

Insensitivity to Growth-Inhibitory Signals

A

Retinoblastoma Protein

1.
Retinoblastoma protein (pRB) has a central role in progression of cell through the G1 phase of the cell cycle.
2.
Action may be lost through deletion or inactivation.
3.
Evidence suggests that alterations leading to the loss of growth suppression by pRB exist in the majority of human cancers.

III

Evasion of Programmed Cell Death

A

p53 Tumor-Suppressor Protein

1.
In healthy cells, it is responsible for temporary arrest of cell growth in response to damage to allow for repair or elimination by apoptosis.
2.
Action may be lost via a diverse array of mechanisms.
3.
Alterations in the p53 pathway exist in the majority of human cancers.

B

Extrinsic Apoptosis Induction

1.
Many tumor cells upregulate programmed death-ligand 1 (PD-L1), which binds to programmed cell death protein 1 (PD-1) on T cells, thereby inactivating immune-mediated killing and permitting tumor escape.

IV

Limitless Replicative Potential

1.
Normal cells carry an intrinsic program that limits their ability to replicate.
- a.
  Independent of cell-to-cell signaling pathways
- b.
  Senescence reached once cells have divided a specified number of times
2.
Loss of tumor suppressor proteins (p53 and pRB) leads to a crisis state.
- a.
  Massive cell death
- b.
  Karyotypic disarray
- c
  One in 10 ⁷ cells achieves the ability to divide ad infinitum, termed immortalization.
3.
Most tumor cells propagated in culture are immortalized.
4.
Telomere maintenance is vital to continued replication of tumor cells.
- a.
  Ongoing maintenance of protective telomere sequences on the ends of chromosomes allows for immortality of cells.
- b.
  Reactivation of telomerase (suppressed in normal human cell types) and a telomerase-independent mechanism (“alternative lengthening of telomeres”) allow for indefinite proliferation of cells.

V

Sustained Angiogenesis

1.
Tumors cannot exceed diameters of 2 mm without acquiring a blood supply.
2.
Solid tumors secrete proangiogenic factors.
- a.
  Vascular endothelial growth factor (VEGF)
- b.
  Basic and acidic fibroblast growth factor
- c.
  Platelet-derived growth factor
- d.
  anti-VEGF (Avastin)—angiogenesis inhibitor first approved for treatment of colon cancer
3.
Tumors may also downregulate antiangiogenic proteins.
- a.
  Thrombospondin-1, which binds to CD36
- b.
  Interferon-β

VI

Tissue Invasion and Metastasis

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