Hallmarks of Cancer: Sustaining Proliferative Signaling

The Fundamentals of Cancer• The ability of cancer

cells to sustain chronic proliferation is fundamental

• Allows cancer cells to grow into tumors, metastasize, and invade other regions of the body

(Hanahan and Weinberg, 2011)

Propagation of Normal Cells vs. Cancer Cells

The Big Question

• How do cancer cells acquire the ability to replicate continuously?

Sustained Proliferative Signaling• Cancer cells maintain

constant growth through sustaining proliferative signaling

• Deregulation of cell signaling pathways allows cancers cells to upregulate growth signals and downregulate anti-growth signals

The Stages of Cell Signaling1. Reception: Binding between a ligand molecule

and receptor; highly specific

2. Transduction: conversion of a signal to a form that can bring about a specific response via phosphorylation cascade, protein kinases, and second messengers

3. Response: Regulation of gene expression or cytoplasmic activities

Stages of Cell Signaling

Mechanisms of Proliferative Signaling

• Normal cells require mitogenic growth signals in order to proliferate

• Cancer cells acquire growth signal autonomy in a variety of ways

(Hanahan and Weinberg, 2011)

Production of Growth Signals

• Cancer cells produce their own growth signals• Ability to synthesize growth factors and

signaling molecules to which they are responsive (Fedi et al., 1997)

• Creates positive feedback loop for cell growth• Example: Production of PDGT and TGF-alpha

by glioblastomas and sarcomas (Fedi et al., 1997)

Overexpression of Receptors

• Cancer cells over-express receptor proteins, in particular, growth factor receptors

• Causes cancer cells to become hyper-responsive to external growth signals (Fedi et al., 1997)

• Example: Epidermal GF receptor is up-regulated in stomach, brain, and breast tumors (Slamon et al.,1987)

Ligand-Independent Signaling• Over-expression of growth factor receptors

induces ligand-independent signaling (DiFoire et al., 1987)

• No need for signaling molecules to trigger cell division and growth

• Same result achieved through structural alterations of receptor proteins

• Example: Modified EGF receptor induces non-stop signaling (Fedi et al., 1997)

Downstream Alterations

• Downstream alterations of intracellular circuits can trigger proliferative signaling

• SOS-Ras-Raf-MAP Kinase growth pathway• Example: In 25% of tumors, Ras proteins are

modified to induce mitogenic signals downstream of the GF receptor (Medema and Bos, 1993)

Recruitment of Normal Cells

• Cancer cells recruit normal cells neighbors to supply growth factors and signals

• Cancer cells stimulate normal cells to release growth factors into the tumor microenvironment (Cheng et al., 2008; Bhowmick et al., 2004)

• Key role of fibroblasts and endothelial cells• Paracrine signaling vs. endocrine signaling

The Genetic Basis of Unregulated Growth: Mutation

• Genetic mutation leads to cancer

• Over-expression of oncogenes, under-expression of tumor suppressor genes

• Mutations in oncogenes mimic growth signaling (Hanahan and Weinberg, 2000)

• About half of human tumors have mutant Ras oncogenes (Kinzler and Vogelstein, 1996)

New Research

• Somatic mutations activate additional downstream pathways

• About 40% of human melanomas contain mutations affecting B-Raf proteins in the MAP-kinase pathway (Davies and Samuels, 2010)

• Defects in negative-feedback loops promote proliferative signaling

• Mutations in Ras oncogenes compromise GTPase activity, which regulates proliferative signaling (Hanahan and Weinberg, 2011)

ReferenceHanahan, D., & Weinberg, R. A. (2011). Hallmarks of Cancer:

The Next Generation. Cell, 144, 646-674.

Hanahan, D., & Weinberg, R.A. (2000). The Hallmarks of Cancer. Cell, 100, 57-70