Biology Reference
In-Depth Information
Carcinoma
in
situ
Early Invasive Carcinoma
Invasive Carcinoma
MMP contribution to EMT
MMP-mediated escape from the primary tumor
MMP-mediated transition from individual to
collective migration of carcinoma cells
MMP-3
MMP-7
MMP-9
MMP-28
Dissolution of E-cadherin
Loss of cytokeratin
Acquisition of vimentin
Bioavailability of TGF
β
MMP-2
MMP-9
MMP-13
MMP-14
(MT1-MMP)
MMP-15
MMP-16
BM degradation
ECM proteolysis and matrix
remodeling
Matrix micro-and macro-patterning
by leading tumor cells
Invasion of leading tumor cells
“guided” by myofibroblasts
MMP-14
Tumor cell invasion/migration along
MMP-14-modified collagen “tracks”
MMP-induced angiogenic switch and
MMP-mediated angiogenesis
EMT-induced expression of MMPs
MMP-9
Induction of angiogenesis by MMP-9
released by inflammatory neutrophils
and secreted by macrophages
Bioavailability of VEGF and FGF-2
Induction of MMP expression in
activated cancer-associated
fibroblasts
Recruitment of MMP-9-delivering myeloid cells
(monocytes/macrophages, neutrophils,
and mast cells)
Neutrophil and
neutrophil granules
containing MMP -9
Basement membrane
Extracellular matrix
Stromal fibroblast
Activated myofibroblast
Angiogenic blood vessel
Monocyte/macrophage
Carcinoma cell
MMP- 14 (MT1 -MMP)
Fig. 7.1 MMP-mediated mechanisms involved in early stages of carcinoma progression. The
schematic highlights the critical events where MMPs have been shown to induce, mediate, or
govern specific mechanisms during early stages of carcinoma progression, i.e., from the carcinoma
in situ to definitively invasive carcinoma. Carcinoma in situ is regarded as incipient carcinoma
lacking visible signs of epithelial cell invasion beyond the boundaries of basement membrane that
fully surrounds epithelial cell acini. It has been demonstrated that certain MMPs can induce the
invasive phenotype and behavior in carcinoma cells leading to the process collectively described as
epithelial-mesenchymal transition (EMT). Alternatively, MMPs can be induced as a result of EMT.
At this very early carcinoma progression stage, stromal fibroblasts can be already activated and
become myofibroblasts that express proinflammatory factors attracting myeloid cells and ECM-
modifying MMPs. Early invasive stage is manifested by the breaching of basement membrane by
singular MMP-expressing carcinoma cells that escape the primary tumor and actively degrade and
modify (pattern) the surrounding ECM. Migration and invasion of leading carcinoma cells could be
guided by MMP-expressing activated fibroblasts. This stage of carcinoma progression involves the
recruitment of inflammatory myeloid cells, e.g., neutrophils and monocytes/macrophages deliver-
ing MMP-9 that triggers the angiogenic switch. The invasive carcinoma stage is associated with
MMP-mediated transition from individual cell migration to collective cell invasion, manifested by
“Indian files” or multicellular strands. The proteolytic activity of MMP-14 (MT1-MMP) has been
most clearly implicated in this transition. The induction of tumor angiogenesis by proteolytic
release and activation of proangiogenic factors has been linked mainly to the enzymatic activity
of inflammatory MMP-9
individual cells and cell aggregates in this study was linked to the ability of ovarian
carcinomas to form secondary lesions. The invasive spread of carcinoma included
the initial formation of cell aggregates and their subsequent adherence to the
mesenteruim, followed by disaggregation and development of the invasive foci.
Interestingly, in this sequence of apparently opposing events, i.e., detachment-
aggregation-disaggregation, the individual underlying processes were similarly
dependent on the proteolytic activity MT1-MMP (Moss et al.
2009
).
