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Summary SSA13 The tumor microenvironment
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Summary and WG answers of SSA13 The tumor microenvironment of the course MBO (molecular biology and oncology) at University of Leiden.
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SSA13 The tumormicroenvironment: Not an
innocent by-stander
Chapter 13 Weinberg
The non-neoplastic cells (the stroma) can account for up to 90% of the tumor mass. These
are active and collaborate with the neoplastic epithelial cells in the carcinoma.
13.1 Normal and neoplastic epithelial tissues are formed
from independent cell types
The neoplastic epithelial cells are the true carcinoma cells. Stromal cells include fibroblasts,
myofibroblasts, endothelial cells, pericytes, smooth muscle cells, adipocytes, macrophages,
lymphocytes and mast cells. Some cells are active participants in for example invasiveness
and metastasis. Others, like cells of the immune system, may try to eliminate the tumor.
The diverse stromal cell types are from a different lineage and are thus biologically different
from the transformed epithelial cells. One explanation for the presence of the stromal cells is
that they might be remnants from the regular stroma. A more likely explanation is that there
is heterotypic signaling between the cancer cells and the stromal cells. They thus influence
and need each other.
In normal tissue the heterotypic signaling depends in large part of:
1. Mitogenic growth factors
2. Growth inhibitory signals like TGF-B
3. Trophic factors
These signals go into the ECM and then work over a short distance
One type of evidence for this was auto-transplantation of skin cancer. If only the epithelial
cells were transplanted, there was no successful tumor growth. However, when also the
stromal cells were transplanted it was.
Carcinoma cells release growth factors, cytokines and chemokines that recruit immune cells
to the tumor-associated stroma. These then give an inflammatory response which involved
release of TNF-alpha and prostaglandins which makes the cells proliferate and induces
angiogenesis.
Carcinoma cells also often release PDGF and in response the stromal cells will then release
IGF-1 which benefits growth and survival of the cancer cells.
The stromal and epithelial cells in normal epithelial tissue also collaborate via the ECM.
Proteoglycans in the basement membrane can increase hydration which allows for longer
term storage of released factors. Healthy epithelial cells need to be tethered to the basement
membrane for their survival.
Endothelial cells which form the lining of vessels as well as the lymphatic ducts are vital
components of the neoplastic stroma. Proliferation of the endothelium is stimulated by both
the stroma and the neoplastic epithelium. They provide nutrients and oxygen and form a
, route to spread. The endothelial cells will also release factors that stimulates proliferation of
nearby non-epithelial cells. In addition, they release PDGF and HB-EGF which enables them
to attract pericytes and vascular smooth muscle cells. The pericytes can release VEGF and
Ang-1 which provides survival signals for the endothelial cells and give more stability to the
vessels.
Even in metastasis, stromal cells can be seen. This indicates that it is thus necessary for the
tumor to recruit these stromal cells and encourage their proliferation. It can also be that
metastatic cells settle in an existing stroma.
The acquired traits of the transformed cells reduce the dependence on the stroma, but it
does not eliminate it. Still, there are some cancers that seem to be really dependent on the
stroma, but also some that are completely not (ascitic tumors).
13.2 The cells forming cancer cell lines develop without
heterotypic interactions and deviate from the behavior of
cells within human tumors
The dependence of carcinoma cells on stromal support complicates in vitro research.
Therefore, cells are often derived from tumor biopsies. However, it is difficult to keep all
stromal cells alive in culture. They also respond differently to the serum-associated factors.
The development of anti-cancer therapies has been imperfectly served by use of existing
human cancer cell lines. When these grow in immunocompromised mice you can test drugs
in these mice. However, the success in these xenograft models has only limited predictive
value for the actual clinical response. One explanation is that the cell lines used sometimes
have only little resemblance to the cells encountered in the clinic. Moreover, the cell lines
have been propagated in vitro under very different circumstances under which absence of
the stroma. The tumors also are often transplanted at an ectopic site instead of their
orthotropic site. Better would be to implant actual tumor fragments, however this takes too
long and is very labor intensive.
13.3 Tumors resemble wounded tissues that do not heal
Heterotypic signaling is a big part of the carcinoma biology. Biological models actually ignore
this. Many of these signals are not exchanged by normal undamaged tissue. However, it is
not completely unique to tumors. It resembles much of what is seen in wounds. They thus
activate a normal biological program and exploit this.
In would healing, there is platelet aggregation and these release PDGF and TGF-B. It also
causes vasoactive factors to be released which increases permeability of vessels. This helps
to get fibrogen molecules from the plasma which can then make a scaffolds. PDGF that is
released attracts fibroblasts and stimulates their proliferation. TGF-B activates the fibroblasts
so that they become myofibroblasts which secrete MMPs. MMPs can also be produced by
recruited macrophages. MMPs have a zinc ion for their protease activity. Activated
fibroblasts also secrete mitogens which stimulates proliferation of certain epithelial cells.
Once released, the MMPs will degrade the ECM. This causes remodeling and causes
release of stored factors and this activates them.
The growth factors released by the platelets also leads to monocyte recruitment. These not
only remove debris, but also release factors like FGF and VEGF which leads to
neoangiogenesis.
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