Dialogue Replaces Monologue: Chapter 13 Dialogue Replaces Monologue: Heterotypic Interactions and the Biology of Angiogenesis ~ 13.1 – 13.10 ~ Jun 12, 2007

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

Squamous cell carcinoma of the oral cavity α-smooth muscle actin + CD34 + fibrocytes CD117 + mast cells myofibroblasts Figure 13.3b,c,d The Biology of Cancer (© Garland Science 2007)

carcinoma colorectal adenocarcinoma non-small-cell-lung carcinoma colorectal adenocarcinoma CD4 + T lymphocytes CD11b + monocytes Figure 13.3a The Biology of Cancer (© Garland Science 2007)

Heterotypic interaction and signaling In normal tissues, heterotypic signals depend on the exchange of 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. Figure 13.4 The Biology of Cancer (© Garland Science 2007)

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.

13.2 The cells forming cancer cell lines develop without heterotypic interactions and deviate from the behavior of cells within human tumors primary carcinoma tumors grown in immuno-compromised severe combined immunodeficiency (SCID) mice

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

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)

Necrosis within a tumor stroma Figure 13.28 The Biology of Cancer (© Garland Science 2007)

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.

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

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) Figure 13.37 The Biology of Cancer (© Garland Science 2007)

The angiogenic switch 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. Figure 13.38a The Biology of Cancer (© Garland Science 2007)

Activation of VEGFs by MMP-9 (matrix metalloproteinase-9) (extracellular matrix) Angiogenic switching does not occur in VEGF-deficient Rip-Tag mice. Figure 13.38b The Biology of Cancer (© Garland Science 2007)

Table 13.2 The Biology of Cancer (© Garland Science 2007)

Angiogenesis and invasiveness are tightly coupled capillaries Figure 13.41 The Biology of Cancer (© Garland Science 2007)

Patients whose tumors have a higher microvessel count have a lower probability of survival breast cancer Figure 13.42a The Biology of Cancer (© Garland Science 2007)

Patients whose tumors express VEGF have a lower probability of survival breast cancer Figure 13.42b The Biology of Cancer (© Garland Science 2007)

Table 13.3 The Biology of Cancer (© Garland Science 2007)

Thrombospondin, endothelial cell survival and tumorigenesis 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. Figure 13.45a The Biology of Cancer (© Garland Science 2007)

Balancing the angiogenic switch Figure 13.46 The Biology of Cancer (© Garland Science 2007)

Table 13.4 The Biology of Cancer (© Garland Science 2007)

Heterotypic interactions as targets for future cancer therapies Figure 13.49 The Biology of Cancer (© Garland Science 2007)