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

2. 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

3. 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)

4. 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)

5. 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 The Biology of Cancer (© Garland Science 2007)

6. 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.

7. 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

8. 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

9. 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)

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

11. 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.

12. 13.7 – 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

13. 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 The Biology of Cancer (© Garland Science 2007)

14. 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)

15. 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)

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

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

18. 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)

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

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

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

22. 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)

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

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

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