Robert A.
Weinberg
The Biology of Cancer
Second Edition
CHAPTER 7
Tumor Suppressor Genes
Copyright © Garland Science 2014
Cell fusion experiments test whether cancer
phenotype is dominant or recessive
Most cancers that are NOT caused by tumor viruses have a recessive phenotype.
This lead to the search for tumor suppressor genes.
• The retina is a multilayered
structure.
• Differentiated photoreceptors
(rods and cones) are located
at the back of the eye (bottom
of the figure).
• Precursor cells are found at
the front (top).
Retinoblastoma
• Rare childhood cancer
• Familial form often occurs bilaterally
• Sporadic form usually occurs unilaterally
Knudson’s Two-Hit Hypothesis
Loss-of-heterozygosity (LOH)
by mitotic recombination
Loss-of-heterozygosity (LOH)
by gene conversion
Loss-of-heterozygosity (LOH)
by nondisjunction
Discovery of the Rb gene
Using polymorphism in esterase D gene to
demonstrate LOH
In some tumors, second “hit” deleted
Rb sequences.
Using restriction fragment length polymorphism
(RFLP) identify regions of LOH
Regions undergoing LOH in colorectal tumors
Smad4
Schmierer and Hill, Nature Reviews Mol Cell Biol, 2007
Hypothesis: Cancer cells may produce their
own growth factors
www.rndsystems.com
Discovery of TGF-b
www.rndsystems.com
Structure of TGF-b
Ten Dijke and Arthur,
Nature Reviews Mol Cell Biol 2007
www.bio-techne.com
Dual role of TGF-bs in tumorigenesis
Wakefield and Roberts, 2002
Discovery of Bone Morphogenetic Proteins
(BMPs)
Discovery of TGF-b Receptors
In 1993:
Vertebrate C. elegans
Extracellular
TGFb
Type II DAF-4
Receptor
Intracellular
Nucleus Nucleus
Massagué, others Riddle
Discovery of Smads
Heterotrimer Model for Smads (Dwarfins)
Savage et al. PNAS, 1996
Human Tumor Suppressor DPC4 = Smad4
Overview of TGF-b Signaling
Receptor-regulated Smads
(R-Smads)
Inhibitory Smads
(I-Smads)
Common Mediator Smads
(Co-Smads)
Ten Dijke and Arthur, Nature Reviews Mol Cell Biol 2007
Smad Structure
Euler-Taimor and Heger, Cardiovascular Res 2006
Structure of Smad2/4 MH2 Heterotrimer
Chacko et al., Mol Cell 2004
Smad Nucleocytoplasmic Shuttling
Schmierer and Hill, Nature Reviews Mol Cell Biol, 2007
“Dual-address”
Signaling Pathways
Canonical and Noncanonical TGF-b Signaling
Wakefield and Roberts, 2002
TGF-b as a Tumor Suppressor
In normal epithelial, neuronal and hematopoietic cells, TGF-b limits cell proliferation by
repressing Myc and inducing expression of CDK inhibitors p15 and p21.
Meulmeester and ten Dijke, J Pathology 2011
TGF-b as a Tumor Suppressor
TGF-b controls tumor progression at early stages of tumor development by inhibiting the
production of growth factors in surrounding tumor stroma.
Meulmeester and ten Dijke, J Pathology 2011
How tumor cells evade TGF-b tumor
suppressive effects
Wakefield and Roberts, 2002
TGF-b as a Tumor Promoter
TGF-b promotes epithelial-to-mesenchymal transition (EMT),
allowing tumor cells to metastasize.
Meulmeester and ten Dijke, J Pathology 2011
Huang and Blobe, Biochem Soc Trans 2016
TGF-b as a Therapeutic Target
• Antisense oligonucleotides
– Trabedersen (anti-TGF-b2) in phase III clinical trials for high-grade glioma,
pancreatic cancer and malignant melanoma
• Ligand traps (soluble TGF-b receptors or neutralizing antibodies)
– Fresolimumab (TGF-b monoclonal antibody) in phase II clinical trials for
glioma, metastatic breast cancer and pleural malignant mesothelioma
• Small molecular inhibitors
– Galunisertib/LY2157299 (Type I receptor kinase inhibitor) in phase II clinical
trials for glioblastoma, hepatocellular carcinoma, non-small cell lung cancer,
and pancreatic cancer
BANGs (BMP/Activin/Nodal/GDF) as
Therapeutic Targets
ACE-041 Soluble receptor ACE-011 Soluble receptor
PF-03446962 Receptor Ab
Wakefield and Hill, Nature Reviews Cancer 2013
