NG2/CSPG4-collagen type VI interplays putatively involved in the microenvironmental control of tumour engraftment and local expansion

Abstract

In soft-tissue sarcoma patients, enhanced expression of NG2/CSPG4 proteoglycan in pre-surgical primary tumours predicts post-surgical metastasis formation and thereby stratifies patients into disease-free survivors and patients destined to succumb to the disease. Both primary and secondary sarcoma lesions also up-regulate collagen type VI, a putative extracellular matrix ligand of NG2, and this matrix alteration potentiates the prognostic impact of NG2. Enhanced constitutive levels of the proteoglycan in isolated sarcoma cells closely correlate with a superior engraftment capability and local growth in xenogenic settings. This apparent NG2-associated malignancy was also corroborated by the diverse tumorigenic behaviour in vitro and in vivo of immunoselected NG2-expressing and NG2-deficient cell subsets, by RNAi-mediated knock down of endogenous NG2, and by ectopic transduction of full-length or deletion constructs of NG2. Cells with modified expression of NG2 diverged in their interaction with purified Col VI, matrices supplemented with Col VI, and cell-free matrices isolated from wild-type and Col VI null fibroblasts. The combined use of dominant-negative NG2 mutant cells and purified domain fragments of the collagen allowed us to pinpoint the reciprocal binding sites within the two molecules and to assert the importance of this molecular interaction in the control of sarcoma cell adhesion and motility. The NG2-mediated binding to Col VI triggered activation of convergent cell survival- and cell adhesion/migration-promoting signal transduction pathways, implicating PI-3K as a common denominator. Thus, the findings point to an NG2-Col VI interplay as putatively involved in the regulation of the cancer cell-host microenvironment interactions sustaining sarcoma progression.

NG2 proteoglycan-dependent recruitment of tumor macrophages promotes pericyte-endothelial cell interactions required for brain tumor vascularization

“…However, the proteoglycan is also expressed by tumor cells in several types of cancer, including melanoma, [41][42][43][44] glioblastoma, 38,45,46 sarcoma, 47 myeloid leukemia, 48 and triple-negative breast cancer. 49 In all cases, increased NG2 expression by tumor cells is associated with enhanced tumor progression and worsened patient prognosis.…”

Collagen VI at a glance

“…The enhanced ColVI expression favors tumor development and progression through various mechanisms. On the one hand, ColVI directly acts on cancer cells, where it binds to NG2, activating the Akt-GSK-3β-β-catenin-TCF-LEF axis (Iyengar et al, 2005) and the phosphoinositide 3-kinase (PI3K) pathway (Cattaruzza et al, 2013), or induces epithelial-mesenchymal transition (Park and Scherer, 2012), thus promoting tumor growth and metastasis. On the other hand, ColVI is an important pro-tumorigenic factor acting on the tumor microenvironment, where it promotes tumor inflammation and angiogenesis by targeting macrophages and endothelial cells, respectively (Park and Scherer, 2012;Chen et al, 2013).…”

Functional roles of CSPG4/NG2 in chondrosarcoma

“…; Cattaruzza et al . ). The aim of this study was to investigate the possible roles of CSPG4/NG2 in chondrosarcomas and to establish whether this molecule may have potential for targeted therapy.…”