Page 371 - Read Online

Xiong et al. ECM in tumor progression

Figure 1: Stroma cell-derived extracellular matrix (ECM) and cancer cell-derived ECM collectively support cancer cell proliferation,
invasion, and metastasis. ECM: extracellular matrix; BMDC: bone marrow-derived cells; PLOD: lysyl-hydroxylase; LOX: lysyl oxidase

LOX activation reduces collagen fibril formation and significantly upregulated. Gene expression profile
[65]
ECM stiffness, which depresses focal adhesions and studies from other labs also reveal that expression of
PI3K activity, and consequently suppresses cancer genes involved in synthesis and organization of ECM
cell invasion. These results indicate that collagen are upregulated in the epithelium of invasive cancer
[54]
modification enzymes P4Hs, PLODs, and LOXs play cells. [53,63,66-68]
critical roles in cancer cell metastasis.
LAMC2 (gamma 2 chain gene of laminin 5) is highly
CANCER CELLS ARE CRITICAL SOURCES expressed in invasive cancer cells in mammary, colon,
OF TUMOR ECM melanoma and sarcoma tumora. [24-26,69] Hyaluronan
synthesis is increased in a variety types of cancer cells,
The cellular components of tumor stroma include including breast tumor, melanoma tumor, and myeloma
fibroblasts, endothelial cells, fat cells, and immune tumor. [22,23,27] Thrombospondin-1 is expressed in the
[70]
cells. It has been shown that cancer-associated stroma and cancer cells. TNC, a key metastatic niche
fibroblasts produce and regulate the ECM remodeling molecule required for the metastasis initiation, is also
in cancer tissue, and the roles of cancer cells in ECM expressed in breast tumor cells and stroma cells. [8,16,18]
deposition have not been appreciated until recently. Dr. Collagens are mainly synthesized by cancer-associated
Hynes’s laboratory investigated matrisome (ECM and fibroblasts in breast cancer, but cancer cells are also
[63]
ECM-associated proteins) in colon tumor tissues, lung an important source of the collagen. In addition, the
tumor tissues, and human breast cancer tissue. [20,21] expression of collagen synthesis regulating enzymes
They found that ECM components in tumor matrix P4H and PLOD is induced by the HIF-1 pathway in
are derived from cancer cells and stromal cells, cancer cells. [30,31,51,64] We have summarized ECM
and many of them are only expressed by cancer proteins and ECM-related enzymes derived from the
cells, including Col19A1, Col22A1, Col7A1, LAMA4, stroma cells and cancer cells in Table 1. This evidence
LAMB1, LTBP1, LTBP3, LTBP4, TINAGL1, and ECM clearly shows that cancer cells are a major source of
regulators galectin 1 (LGALS1) and PLOD1. [20,21] Gene tumor ECM.
expression analysis of drug-resistant breast cancer
cells has found that 25 ECM components’ genes CANCER CELL-DERIVED ECM IN CANCER
(including collagen, fibronectin, syndecan, and laminin) PROGRESSION AND METASTASIS
and integrin ligands are upregulated in drug-resistant
breast cancer cells. Gene expression analysis of ECM deposited by cancer cells is crucial for cancer
[28]
drug-resistant ovarian cancer cells also discovered progression and metastasis. It has been shown that
that molecules in ECM networks, including COL3A1, inhibition of LOX expression in cancer cell represses
COL5A2, COL15A1, and LOX, among others, are very cell adhesion, migration, and invasion. [29,71] Hyaluronan
Journal of Cancer Metastasis and Treatment ¦ Volume 2 ¦ September 18, 2016 361