chapter 13 dialogue replaces monologue: heterotypic interactions and the biology of angiogenesis ~...
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Chapter 13
Dialogue Replaces Monologue:Heterotypic Interactions and the
Biology of Angiogenesis
~ 13.1 – 13.10 ~
Jun 12, 2007
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13.1 Normal and neoplastic epithelial tissues are formed from interdependent cell types
In carcinomas,
epithelial cells → carcinoma cells
stromal cells :
fibroblasts, myofibroblasts, endothelial cells, pericytes, smooth muscle cells, adipocytes, lymphocytes, macrophages, and mast cells
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Figure 13.3b,c,d The Biology of Cancer (© Garland Science 2007)
α-smooth muscle actin + CD34 + fibrocytes CD117 + mast cells myofibroblasts
Squamous cell carcinoma of the oral cavity
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Figure 13.3a The Biology of Cancer (© Garland Science 2007)
non-small-cell-lungcarcinoma colorectal adenocarcinoma
CD4 + T lymphocytes CD11b + monocytes
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Figure 13.4 The Biology of Cancer (© Garland Science 2007)
Heterotypic interaction and signaling
In normal tissues, heterotypic signals depend on the exchange of
(1) Mitogenic growth factors
HGF, TGF-α, PDGF, etc.
(2) Growth-inhibitory signals
TGF-β
(3) Trophic factors (favor cell survival)
IGF-1, IGF-2, etc.
All of the heterotypic interactions needed to maintain normal tissue function may continue to operate within carcinomas.
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Tumor cells and neighboring stromal cells may express paired ligands /receptors
Carcinoma cells express: e.g., PDGF, IGF-1R, IGF-2R,
CXCLR12, MET (HGFR), etc.
Stromal cells express : e.g., PDGFR, IGF-1, IGF-2, CXCL12,
HGF, VEGF/VEGFR, Ang-1, etc.
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13.2 The cells forming cancer cell lines develop without heterotypic interactions and deviate from the behavior of cells within human tumors
tumors grown in immuno-compromised severe combined immunodeficiency (SCID) mice
primary carcinoma
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13.3 Tumors resemble wounded tissues that do not heal
13.4 Stromal cells are active contributors to tumorigenesis
13.5 Macrophages represent important participants in activatng the tumor- associated stroma
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13.6 Endothelial cells and the vessels that they form ensure tumors adequate access to the circulation
- O2 can only effectively diffuse 0.2 mm through living tissues. Cells located within this radius from a blood vessel can rely on diffusion to guarantee them O2. Those situated further away suffer from hypoxia.
distance from vessel (μm)
Figure 13.27d The Biology of Cancer (© Garland Science 2007)
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Figure 13.28 The Biology of Cancer (© Garland Science 2007)
Necrosis within a tumor
stroma
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- Myofibroblasts in the tumor-associated stroma can release chemotactic signals, such as stromal cell-derived factor 1 (SDF-1) /CXCL12, which helps to recruit circulating endothelial precursor cells into the stroma. This recruitment is also aided by the release of vascular endothelial growth factor (VEGF), a key angiogenic factor.
- Production of VEGF is governed by the avalability of O2, and VEGF functions as a ligand of VEGF receptor displayed on the surface of endothelial cells.
- Other factors participating in angiogenesis are:
TGF-βs, basic fibroblast growth factor (bFGF), PDGF, interleukin-8 (IL-8), angiopoitin, angiogenin, etc.
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13.7 – 13.10 Angiogenesis
- Most of tumors are unable to attract blood vessels initially.
- As tumors grow, the resulting hypoxia triggers p53-dependent apoptosis.
- At some point during tumor progression, some pre-neoplastic cells acquire the ability to provoke neoangiogenesis.
- The change in the behavior of these small tumor masses is called “angiogenic switch”, a clearly important step in tumor progression.
- “angio” : blood and lymph vessel
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Figure 13.37 The Biology of Cancer (© Garland Science 2007)
Only vascularized tumors can grow to large sizes in Rip-Tag transgenic mouse model
Rip-Tag transgenic mice: transgenic in SV40 large and small T antigen genes regulated by the insulin promoter
(an animal model for carcinogenesis & angiogenesis)
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Figure 13.38a The Biology of Cancer (© Garland Science 2007)
The normal islet cells are poorly vascularized and is sustained largely through diffusion from the microvessels surrounding it.
Following angiogenic switch, a dramatic induction of vessel formation promotes tumor growth.
The angiogenic switch
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Figure 13.38b The Biology of Cancer (© Garland Science 2007)
Activation of VEGFs by MMP-9
(extracellular matrix)
Angiogenic switching does not occur in VEGF-deficient Rip-Tag mice.
(matrix metalloproteinase-9)
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Table 13.2 The Biology of Cancer (© Garland Science 2007)
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Figure 13.41 The Biology of Cancer (© Garland Science 2007)
Angiogenesis and invasiveness are tightly coupled
capillaries
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Figure 13.42a The Biology of Cancer (© Garland Science 2007)
Patients whose tumors have a higher microvessel count have a lower probability of survival
breast cancer
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Figure 13.42b The Biology of Cancer (© Garland Science 2007)
Patients whose tumors express VEGF have a lower probability of survival
breast cancer
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Table 13.3 The Biology of Cancer (© Garland Science 2007)
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Figure 13.45a The Biology of Cancer (© Garland Science 2007)
Thrombospondin, endothelial cell survival and tumorigenesis
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Figure 13.45a The Biology of Cancer (© Garland Science 2007)
Thrombospondin, endothelial cell survival and tumorigenesis
p53 can induce the transcription of TSP1 gene.
Ras causes shutdown of TSP1 gene.
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Figure 13.46 The Biology of Cancer (© Garland Science 2007)
Balancing the angiogenic switch
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Table 13.4 The Biology of Cancer (© Garland Science 2007)
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Figure 13.49 The Biology of Cancer (© Garland Science 2007)
Heterotypic interactions as targets for future cancer therapies