are also responsible for wound repair.
However, the cancer-associated
fibroblasts are functionally and phenotypically distinct from the normal
fibroblasts which are in the same tissue but not in tumour microenvironment.
within the tumour stroma are identical to the activated fibroblasts in
wounds by their spindyloid appearance and the expression of ?-SMA . They are distinct in the sense that CAFs are
perpetually activated neither reverting to normal phenotype nor undergoing
apoptosis and elimination. There are several theories regarding the origin of
CAFs . Firstly, the activation of the tissue resident fibroblasts and secondly,
the local cancer cells or epithelial cells undergoing epithelial-to-mesenchymal
transition ( EMT) or the migration and
activation of a marrow-derived cell .
Experimentally, factors such as TGF-? can induce normal fibroblasts to express ?-SMA. However, it is not clear that these experimentally
activated cells acquire other characteristics of CAFs and also if the phenotype
will be stable. The second theory is the EMT . EMT is the biologic process in
which epithelial cells lose their cell-to-cell polarity and cell-cell adhesion
and gain migratory and invasive properties to become mesenchymal stem cells.
Although EMT of cancer cells to CAFs is unlikely to contribute towards majority
of cells within the tumour , there is an alternate proposition that EMT of
surrounding normal epithelial cells may be an additional source of cells for
CAF formation. Recent studies have also shown that bone marrow-derived
precursor cells invade tumours and function as CAFs . It is not clear whether
these cells are activated as a result of influence of the tissue environment or
if they are a subset of cells within the marrow with an already activated
phenotype and are recruited to the site of tumours.
CAFs produce many growth factors like
transforming growth factor (TGF-?) , hepatocyte growth factor ,
insulin growth factor ½ , which lead to
proliferation and invasion of cancer cells . They also secrete
chemokines such as monocyte chemotactic protein 1, interleukin 1 to stimulate
proliferation of tumour cells.
CAFs also produce MMPs mostly MMP-9,
MMP-2 and other matrix modifying enzymes which include urikinase- type
plasmonigen activator(uPA) that degrade the ECM
and support tumour invasion and metastasis . CAFs also produce SDF-1
that stimulates tumour growth directly. SDF-1 signaling can also stimulate
angiogenesis by recruiting EPCs into the tumour stroma.
IMMUNE CELLS OF THE STROMA
Immune cells like monocytes, macrophages,
neutrophils, lymphocytes are recruited by the tumour cells and thereafter, reside
in the tumour stroma. Infact, at the early stage of tumorigenesis the immune
system of the host can eliminate a significant portion of the premalignant
cells even before their initiation. However, sometimes the cancerous cells
evade the immune system and stay at a dormant stage for a long time called the
equilibrium stage. When these cells are mutated they escape the immune defence
system and start to proliferate rapidly to form a tumour. In other words, the
tumour microenvironment is in an