Molecular and clinical profiles of syndecan-1 in solid and hematological cancer for prognosis and precision medicine

Abstract

Syndecan-1 (SDC1, CD138) is a key cell surface adhesion molecule essential for maintaining cell morphology and interaction with the surrounding microenvironment. Deregulation of SDC1 contributes to cancer progression by promoting cell proliferation, metastasis, invasion and angiogenesis, and is associated with relapse through chemoresistance. SDC1 expression level is also associated with responses to chemotherapy and with prognosis in multiple solid and hematological cancers, including multiple myeloma and Hodgkin lymphoma. At the tissue level, the expression levels of SDC1 and the released extracellular domain of SDC1 correlate with tumor malignancy, phenotype, and metastatic potential for both solid and hematological tumors in a tissue-specific manner. The SDC1 expression profile varies among cancer types, but the differential expression signatures between normal and cancer cells in epithelial and stromal compartments are directly associated with aggressiveness of tumors and patient's clinical outcome and survival. Therefore, relevant biomarkers of SDC signaling may be useful for selecting patients that would most likely respond to a particular therapy at the time of diagnosis or perhaps for predicting relapse. In addition, the reciprocal expression signature of SDC between tumor epithelial and stromal compartments may have synergistic value for patient selection and the prediction of clinical outcome.

Keywords: CD138; biomarker; cancer; personalized medicine; syndecan.

Figure 1. Model for SDC1 function under normal and cancer conditions

A. SDC1 binds to ECM proteins and/or growth factors through its heparan sulfate chains, and it binds to cytoskeletal proteins for cell anchorage B. SDC1 acts as a coreceptor that facilitates interaction between growth factors and their receptors and enhances cancer mitogenic signaling C. Shed SDC1 (sSDC1) enhances the interaction between growth factors and their receptors in cancer or acts as a decoy receptor D. Nuclear SDC1 controls gene expression in cancer.

Figure 2. Model for putative roles of SDC1 in Hodgkin's lymphoma

A. SDC1 facilitates autocrine interaction between growth factors and their cognate receptors and enhances mitogenic signaling in Hodgkin-Reed-Sternberg (HRS) cancer cells B. Shed SDC1 (sSDC1) binds to growth factor VEGF and bFGF complexes with VEGFR and FGFRs in endothelial cells and promotes angiogenesis C. Shed SDC1 (sSDC1) binds to growth factors to interact with cognate receptors on another HRS cell (paracrine effect).

Figure 3. General mechanisms of action of SDC1 pathway inhibitors are depicted