Biomedical Engineering Reference
In-Depth Information
(ECM) on expression of genes linked to cancer phenotypes: cell proliferation and invasion [10]. The role
of the ECM may be local, as fibrotic foci containing higher levels of collagen may facilitate metastasis
and have been correlated with poor prognosis in breast cancers [11].
16.1.2 collagen i and Breast cancer
The ECM is a complex meshwork of proteins (e.g., proteoglycans, collagens, laminin, fibronectin,
entactin) and polysaccharides (e.g., glycosaminoglycans) secreted by cells into the spaces between
them. Components of the ECM can bind to one another and to adhesion receptors on the cell sur-
face, providing both physical scaffolding to support tissues and biochemical cues to regulate cellular
behavior [12]. In the mammary gland, the ECM acts as a signal integrator mediating complex cellular
functions [13].
Collagen is a major component of the ECM within the breast tissue and recently has become an area
of research focus in understanding breast cancer development and risk. The fundamental unit of colla-
gen is tropocollagen, a long (300 nm) triple-helix protein structure. Cleavage of the pro-peptide termini
allows collagen to self-assemble to form collagen fibrils with diameters of 0.5−3 μm. There are 28 dif-
ferent types of collagen in the body, most made up of triple-helical monomeric units that organize into
supramolecular structures [14,15]. In particular, collagen I is the most abundant collagen, and is known
to have a significant effect on mammary morphogenesis and tumorigenesis [12,16−19].
Collagen regulates cell and tissue function through physical scaffolding, as a biochemical ligand and
through its mechanical properties [11]. Changes in the structure and function of ECM and collagen
have been found to have profound effects on cell behavior and tumor formation, such as enhancing
tumorigenesis through regulating interactions between epithelial cells and the stroma in the breast [6].
Changes in collagen structure can lead to increased rigidity of the ECM, resulting in altered signaling,
differentiation, proliferation, and migration of cells. Increased matrix stiffness activates several signal-
ing pathways, including the Ras−MAPK pathway, which promotes growth of epithelial cells [10,20].
The interaction between cells and the ECM plays an important role in maintaining normal cell behav-
ior [13,21], and the disruption of this interaction is one of the hallmarks of the transition from normal
tissue to malignancy [22,23]. It is still not clear if the breakdown of structure precedes or follows the
invasive transition, but the overexpression of an ECM remodeling enzyme, matrix metalloproteinase 3
(MMP-3), has been shown to stimulate the establishment of a reactive stroma, which is characterized
by increased deposition of collagen I prior to tumor formation [24]. MMP-3 has also been shown to
promote reactive stroma and fibrosis, leading to carcinogenesis in murine mammary glands [25]. The
increased deposition of collagen I, characteristic of a reactive stroma, is just one of several specific col-
lagen I structural changes found in the presence of mammary tumors.
Covalent crosslinking of collagen is a normal part of collagen matrix formation but is often increased
in tumor environments. Crosslinking of collagen fibrils is catalyzed by enzymes such as lysyl oxidase
(LOX). LOX expression can be induced by growth factor signaling as well as hypoxic conditions in
tumor cells [26]. Increased expression of LOX correlates with tumor progression and breast cancer risk,
thus highlighting the role of collagen reorganization in breast cancer [11,27]. Crosslinking of collagen
fibers increases integrin signaling, which has been shown to promote tumor formation [9].
16.1.3 collagen as a cancer Biomarker: tumor Associated collagen
Signatures
In addition to the amount and cross-linking of collagen, changes in the organization and orientation
of collagen fibers have significant effects on cell migration. In normal breast tissue, collagen appears
as curly fibers, while collagen associated with tumors often appears thicker and more linear [11].
Provenzano et al. [17] demonstrated a set of changes that accompany tumor progression, termed tumor
associated collagen signatures (TACS) (Figure 16.1).
