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tumor-associated stromal cells, where they have critical and diverse roles in tumor
progression [reviewed in Bugge ( 2003 )]. Nevertheless, at least as defined by studies
of established tumor cell lines engaging native basement membrane or interstitial
collagen in culture, the complement of proteolytic enzymes that mediate the degra-
dation of basement membrane and interstitial collagens appears to be no different
from that used by normal cells to degrade collagen in a physiological context and it
seems to be limited to the membrane-type MMP collagenases, MMP-14, MMP-15,
and MMP-16 (Hotary et al. 2006 ; Sabeh et al. 2004 ). However, the cell-based assay
system from which these conclusions were derived does not address the contribution
of tumor-associated stromal cells known to express a number of extracellular matrix
degrading enzymes, including secreted collagenases, such as MMP-2 and MMP-13.
Furthermore, tumor cells adopted for continuous growth in culture may be quite
different from their native counterparts in terms of protease expression. Therefore,
the paradigm of tumor cell-produced membrane-type MMPs as the proteolytic
enzymes solely responsible for extracellular collagen degradation in the context of
tumor progression, although both attractive and well supported by data, awaits
definitive confirmation in an in vivo setting [reviewed in Rowe and Weiss ( 2009 )].
3.3 Endocytic Degradation of Collagen
Evidence for the existence of an endocytic pathway for collagen turnover was
obtained already four decades ago by the identification of intracellular inclusions
of phagocytosed collagen in mesenchymal cells associated with cancer, rheumatoid
arthritis, emphysema, and periodontal disease (Cullen 1972 ; Harris et al. 1977 ;
Neurath 1993 ; Soames and Davies 1977 ). Indeed, the endocytic pathway has been
proposed to be the major clearance mechanism for collagen under steady-state
conditions (Everts et al. 1996 ). It is primarily operative in mesenchymal cells and
ultimately results in the complete degradation of the internalized collagen by
lysosomal proteases within the acidified lysosomal environment (Kielty et al.
1993 ; Lee et al. 1996 ; Segal et al. 2001 ). Endocytic collagen turnover is a recep-
tor-dependent process and decisive new insight into endocytic collagen turnover
was made by the identification of a subset of members of the mannose receptor
family and collagen-binding integrins that act as collagen internalization receptors
(Fig. 3.2 ).
3.3.1 Mannose Receptor Family Pathways
The mannose receptor family is a group of four type-I membrane proteins with a
highly conserved domain composition [reviewed in East and Isacke ( 2002 )]. All of
these proteins are endocytic receptors with constitutive internalization through
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