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activation of MMP-2 (Taniwaki et al. 2007 ). These findings demonstrate that
stroma-produced MMP-2, which is a true type IV collagenase, could be the actual
MMP that upon MT1-MMP-mediated activation degrades in vivo deposits of type
IV collagen, a major component of tumor-associated basement membrane. That
MMP-2 can function as a critical protease in BM degradation and remodeling
was shown in another in vivo experimental system, where proteolytic activity of
MMP-2 has been directly linked to the structural alterations in the BM of the renal
epithelium (Cheng et al. 2006 ).
7.4
Individual and Collective Cell Invasion at the Primary
Tumor Site
Morphologically, tumor cells escaping from the primary tumor and invading
surrounding stroma constitute individual cells or the cells assembled in single
cell chains (i.e., Indian files) or multicellular strands (i.e., cohorts). These clus-
tered cells are frequently regarded as collectively migrating/invading cells. The
cohort cell invasion can be viewed as a consequence of incomplete EMT, which
resulted in a partial dissolution of intercellular contacts at the leading edge of
solid tumors and therefore in the directional migration of cancer cells still
connected to each other. Although being visualized in histological sections of
carcinomas for decades (Tarin et al. 2005 ), collective cell invasion has recently
become a focus of intensive experimental reinvestigations aimed to elucidate its
mechanisms in solid tumor dissemination (Gaggioli et al. 2007 ;FriedlandWolf
2008 , 2010 ; Wolf and Friedl 2009 ).
In tissue culture, directed carcinoma cell invasion requires generation of a free
edge, allowing the tumor cells to move coordinately in a direction of free space
formed in the matrix (Hall 2009 ). Therefore, one might assume that collective
cancer cell invasion would require proteolytic preparation of the ECM by the
leading single cells. These invasive cells, individually released from the primary
tumor, are usually viewed as nonpolarized mesenchymal-type cells infiltrating the
stroma and creating the chemoattractive pathways for the ensuing cells, which
invade the stroma in cohorts (Yilmaz and Christofori 2009 ). However, the direc-
tionality of tumor cell infiltration poses a question as to how initially nonpolarized
carcinoma tumor cells eventually get polarized and exploit their complex polarity
machinery to sense the topography of the ECM and perform persistent migration
and invasion.
Only recently, has the multistep processes employed by tumor cells during
transition from individual to collective cancer cell invasion started to be addressed
mechanistically. Using time-resolved multimodal microscopy in vitro, Wolf et al.
( 2007 ) have demonstrated that invasive HT-1080 fibrosarcoma and MDA-MB-231
breast carcinoma cells first break down the sterically impeding collagen fibers using
the collagenase activity of MT1-MMP and then realign the remodeled fibers into
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