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Xiong et al. ECM in tumor progression

INTRODUCTION which is primarily produced by stromal cells, fills in the
interstitial space between cells. The interstitial matrix
Cancer development and progression require is rich in types I, III, V, VI, VII, and XII collagens, as
extensive reorganization of extracellular matrix. [1,2] well as proteoglycans and various glycoproteins such
Extracellular matrix (ECM) is a complex mixture of as TNC and fibronectin. [37]
structural proteins, glycoproteins, and proteoglycans,
which provide not only essential physical scaffolds to Collagen is the most abundant protein in vivo. Forty-
maintain tissue structure but also various biochemical four collagen genes have been identified in the human
signals to modulate cellular function. [3-5] Altering the genome; they generate at least 28 different types of
fine balance of ECM signal is sufficient in the long run collagen. From precursor procollagen to final collagen
to induce breast cancer development and progression. fibril, collagen synthesis process involves several
Increased deposition of collagen and other ECM important modification enzymes. [10,38] Proline and lysine
molecules enhances the cancer tissue stiffness. [6-9] hydroxylation are well characterized modifications
on procollagen, which are catalyzed by two different
Collagens are the most abundant protein in the enzymes: P4H and PLOD. Collagen P4H catalyzes
ECM. [10,11] Collagen fibril has critical function for tumor the formation of 4-hydroxyproline, which is essential
cell growth, migration and metastasis. [12-14] Other ECM to the proper folding of newly synthesized procollagen
components, such as hyaluronan, TNC, and periostin chains. [39,40] PLOD catalyzes the hydroxylation of lysyl
(POSTN), are also highly expressed in metastatic residues in collagen-like peptides, which is critical for
tumor and play important roles in tumor metastasis the formation of intermolecular crosslinks. [41,42] LOX is
niche. [8,15-18] enzyme-catalyzing formation of aldehydes from lysine
residues in collagen after collagen secretion, which
Fibroblasts are considered the major source for ECM is required for collagen fibril formation. [43,44] HSP47
in both normal and malignant tissue. Surprisingly, is a molecular chaperone that promotes maturation
[19]
recent studies showed that cancer cells also produce of collagen molecules by inhibiting the aggregation
a significant quantity of ECM protein during cancer of collagen in endoplasmic reticulum (ER). [45-47]
progression. [20,21] Dr. Hynes’s laboratory, utilizing an The expression of collagen-modification enzymes
elegant proteomic experiment, demonstrated that ECM and molecular chaperone is often associated with
molecules in cancer tissue are deposited by both cancer increased collagen deposition in cancer tissue. [30-33,48-51]
cells and stromal cells. [20,21] ECM proteins, such as Enhanced enzyme activities are often associated with
laminin 5, hyaluronan, and TNC, are highly expressed increased collagen deposition in cancer tissue.
in invasive cancer cells. [22-27] Gene expression analysis
has identified that ECM protein genes are upregulated ECM PLAYS IMPORTANT ROLES IN
in drug-resistant cancer cells. Collagen modification TUMOR PROGRESSION
[28]
enzymes, including prolyl-4-hydroxylase (P4H), lysyl-
hydroxylase (PLOD), and lysyl oxidase (LOX), as ECM is a major component of tumor microenvironment
well as molecular chaperone heat shock protein 47 and plays critical roles in cancer development and
(HSP47), are highly expressed in cancer cells and are progression. Increased ECM proteins deposition
associated with tumor metastasis. [29-33] and crosslink provide necessary biochemical and
biophysical cues to promote cancer cell proliferation,
This review summarizes recent findings about ECM migration, and invasion. [12,52-54] Laminin-322 is
microenvironment in solid tumor. The primary focus specifically localized in the dense fibrotic zone around
is on the role of cancer cells in ECM synthesis and invasive ductal carcinoma, providing a specialized
the function of cancer cell-derived ECM in tumor microenvironment for guiding tumor invasion.
[52]
progression. Gamma 2 chain of laminin 5 (laminin 5 γ2) is highly
expressed in invasive mammary, colon, melanoma,
THE EXTRACELLULAR MATRIX and sarcoma cancer cells. Laminin 5 plays a role
in establishing focal adhesions of cancer cells and
ECM can be classified into two groups: the interstitial contributes to cancer dissemination. [24-26]
matrix and the basement membrane. Basement
[34]
membranes are thin layers of ECM that form the ECM molecules, such as POSTN, fibronectin,
supporting structure under epithelial and endothelial and hyaluronan, are important components of the
cells. Basement membrane has a distinctive metastatic niche. POSTN is a secreted extracellular
[7]
[35]
composition containing type IV collagen, laminins, matrix protein originally identified from mesenchymal
entactins, and proteoglycans. [7,36] The interstitial matrix, cells. [8,16,17] Deletion of POSTN has little effect on normal
358 Journal of Cancer Metastasis and Treatment ¦ Volume 2 ¦ September 18, 2016