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Biology of Cancer


 
 

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


 
 

Figure 13.3b,c,d The Biology of Cancer (© Garland Science 2007) 

 ��-smooth muscle actin +           CD34 + fibrocytes           CD117 + mast cells

       myofibroblasts 

Squamous cell carcinoma of the oral cavity


 
 

Figure 13.3a The Biology of Cancer (© Garland Science 2007) 

non-small-cell-lung

carcinoma                          colorectal adenocarcinoma 

CD4 + T lymphocytes                      CD11b + monocytes


 
 

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-��, PDGF, etc.

(2) Growth-inhibitory signals

       TGF-��

(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.


 
 

   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 

tumors grown in immuno-compromised severe combined immunodeficiency (SCID) mice 

primary carcinoma


 
 

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 (��m) 

Figure 13.27d The Biology of Cancer (© Garland Science 2007)


 
 

Figure 13.28 The Biology of Cancer (© Garland Science 2007) 

Necrosis within a tumor 

stroma


 
 
  •   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-��s, 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


 
 

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)


 
 

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


 
 

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)


 
 

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


 
 

Figure 13.41 The Biology of Cancer (© Garland Science 2007) 

Angiogenesis and invasiveness are tightly coupled 

capillaries


 
 

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


 
 

Figure 13.42b The Biology of Cancer (© Garland Science 2007) 

Patients whose tumors express VEGF

have a lower probability of survival 

breast cancer


 
 

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


 
 

Figure 13.45a 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 13.46 The Biology of Cancer (© Garland Science 2007) 

Balancing the angiogenic switch


 
 

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


 
 

Figure 13.49 The Biology of Cancer (© Garland Science 2007) 

Heterotypic interactions as targets for future cancer therapies


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