title: 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.
authors.affiliation: SOS for Experimental Oncology 2, The National Tumour Institute Aviano-CRO-IRCCS, Aviano (PN), Italy.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Cattaruzza
authors.forename: Pier Andrea
authors.initials: PA
authors.lastname: Nicolosi
authors.forename: Paola
authors.initials: P
authors.lastname: Braghetta
authors.forename: Laura
authors.initials: L
authors.lastname: Pazzaglia
authors.forename: Maria Serena
authors.initials: MS
authors.lastname: Benassi
authors.forename: Piero
authors.initials: P
authors.lastname: Picci
authors.forename: Katia
authors.initials: K
authors.lastname: Lacrima
authors.forename: Daniela
authors.initials: D
authors.lastname: Zanocco
authors.forename: Erika
authors.initials: E
authors.lastname: Rizzo
authors.forename: William B
authors.initials: WB
authors.lastname: Stallcup
authors.forename: Alfonso
authors.initials: A
authors.lastname: Colombatti
authors.forename: Roberto
authors.initials: R
authors.lastname: Perris
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement; D011508:Chondroitin Sulfate Proteoglycans / Q000235:genetics / Q000378:metabolism*; D024142:Collagen Type VI / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008546:Melanoma, Experimental / Q000378:metabolism / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008875:Middle Aged; D034622:RNA Interference; D012509:Sarcoma / Q000378:metabolism / Q000473:pathology*; D015398:Signal Transduction; D012983:Soft Tissue Neoplasms / Q000378:metabolism / Q000473:pathology*; D014162:Transfection; D059016:Tumor Microenvironment / Q000502:physiology*; D000099216:Chondroitin Sulfate Proteoglycan 4
chemical_list: D011508:Chondroitin Sulfate Proteoglycans; D024142:Collagen Type VI; D008565:Membrane Proteins; C101390:CSPG4 protein, human; D000099216:Chondroitin Sulfate Proteoglycan 4
keywords: cell migration; collagen type VI; prognostic biomarker; proteoglycans; sarcoma; tumour–stroma interaction
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