1. Hallmarks of Cancer:
Sustaining Proliferative Signaling

2. 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)

3. Propagation of
Normal Cells vs. Cancer Cells

4. The Big Question
•How do
cancer cells
acquire the
ability to
replicate
continuously?

5. 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

6. The Stages of Cell Signaling
1. 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

7. Stages of Cell Signaling

8. 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)

9. 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)

10. 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)

11. 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)

12. 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)

14. 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

15. 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)

16. 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)

17. Reference
Hanahan, 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