Antithetic roles of proteoglycans in cancer

Abstract

Proteoglycans (PGs), a family of complex post-translationally sculptured macromolecules, are fundamental regulators of most normal and aberrant cellular functions. The unparalleled structural-functional diversity of PGs endows them with the ability to serve as critical mediators of the tumor cells' interaction with the host microenvironment, while directly contributing to the organization and dynamic remodeling of this milieu. Despite their indisputable importance during embryonic development and in the adult organism, and their frequent dysregulation in tumor lesions, their precise involvement in tumorigenesis awaits a more decisive demonstration. Particularly challenging is to ascertain to what extent selected PGs may catalyze tumor progression and to what extent they may inhibit it, implying antithetic functions of individual PGs. Integrated efforts are needed to consolidate the routine use of PGs in the clinical monitoring of cancer patients and to broaden the exploitation of these macromolecules as therapeutic targets. Several PGs have the required attributes to be contemplated as effective antigens for immunotherapeutic approaches, while the tangible results obtained in recent clinical trials targeting the NG2/CSPG4 transmembrane PG urge further development of PG-based cancer treatment modalities.

Syndecan-1 alters heparan sulfate composition and signaling pathways in malignant mesothelioma

“…Syndecan-1 (SDC1) has dual roles in different cancer types by being either an inhibitor or promoter of tumor progression [14]. It is involved in cell proliferation, adhesion, migration, and angiogenesis, but its expression diverges in various tumor types [14][15][16].…”

“…It is involved in cell proliferation, adhesion, migration, and angiogenesis, but its expression diverges in various tumor types [14][15][16]. Generally, SDC1 expression is higher in epithelial malignancies than in mesenchymal tumors.…”

An Integrative Analysis of Meningioma Tumors Reveals the Determinant Genes and Pathways of Malignant Transformation

“…In fact, there is a body of evidence suggesting that statins, which are inhibitors of the HMG-CoA reductase pathway (blocking isoprenoid synthesis), may benefit cancer therapeutics (56). Intermediate filaments are widely used as markers of cancer differentiation and prognosis (57, 58), while proteoglycans are known mediators of tumor cells interaction with their microenvironment and regulators of angiogenesis (59, 60). Oxidoreductase activity plays a role in cancer too, since a recent meta-analysis of 21 studies has shown that polymorphisms in the NAD(P)H quinine oxidoreductase 1 ( NQO1 ) gene are significantly associated with digestive tract cancer risk among Europeans and Asians (61).…”

NG2/CSPG4 Proteoglycan as a Novel Prognostic Indicator and Therapeutic Target in Malignant Cancer

“…Several studies that reduction of cancer cell adhesion and spreading by using monoclonal antibody against the NG2/CSPG4 core protein [49] or enhancement of cancer cell metastasis by using the NG2/CSPG4-null cancer cells [33] suggest that NG2/CSPG4 may be a key factor in integrin-controlled cancer cell adhesion [9,54]. Other signaling pathways such as Wnt [55,56], Prolantin-jak-2-Stat-5 [56], GTPaseRac-Rho [10], ERK1/2 [9] and PI3K/AKT [54] can also be originated by NG2/CSPG4 but are beyond our discuss scope in this review.…”

“…NG2/CSPG4 consists of two chondroitin sulfate proteoglycan components (N-linked 280 kDa, 450 kDa) which express on cell membrane [8]. Since both 280 kDa and 450 kDa comprise of the same core protein but appear to be independently expressed, a challenging would be to ascertain how effectively to what extent to target NG2/CSPG4 in cancer cell matrix action that associates to carcinogenesis [9]. This challenge may be more precise for targeting therapeutics to eventually eliminate progressive malignant cancers and for potential targeting opportunities to develop drugs aimed at theIn the late 1980s, investigators found that NG2/CSPG4 "calms" in progenitor cells but "acts" once the cells make an initial commitment to a particular cellular lineage [21], suggesting that NG2/CSPG4 is not so much a marker for a specific cell type, but is more of a marker for an "activated" (as opposed to quiescent or calm) status of cells.…”