Shed proteoglycans in tumor stroma

Abstract

Cancer cell behavior is not only governed by tumor cell-autonomous properties but also by the surrounding tumor stroma. Cancer-associated fibroblasts, blood vessels, immune cells and the extracellular matrix of the tumor microenvironment have a profound influence on tumor progression. Proteoglycans control various normal and pathological processes, modulating cell proliferation and motility, cell-matrix interactions, immune cell recruitment and angiogenesis. They are major mediators of cancer cell behavior though a dynamic interplay with extracellular matrix components. During cancer progression, their altered expression can promote the activation of several signaling cascades regulating crucial functional properties of cancer cells. Notably, the function of cell surface proteoglycans can be altered by ectodomain shedding, which converts membrane-bound coreceptors into soluble paracrine effector molecules. In this review, we highlight the importance of proteoglycans and their soluble counterparts in cancer progression and the consequences of their interactions with the adjacent stroma. The dynamic interplay among shed proteoglycans and proteolytic enzymes has a significant impact both on tumor cells and their surrounding stroma, with important implications for the diagnosis of this disease and for novel therapeutic approaches. Graphical Abstract Syndecan shedding. The mechanism of shedding involves the proteolytic cleavage of their ectodomain near the plasma membrane by metzincin enzymes, such as metalloproteinases. N-acetylglucosamine-alpha-L-iduronic acid/beta-D-glucuronic acid (HS) chains can be additionally cleaved by heparanase. Syndecan core protein can be further processed by intramembrane enzymatic cleavage. Syndecans are in a dynamic interplay with the extracellular matrix and several receptor-tyrosine-kinases (RTKs) and various growth factors, for which they act as co-receptors, thus mediating numerous signaling pathways.

A shift from membranous and stromal syndecan‐1 (CD138) expression to cytoplasmic CD138 expression is associated with poor prognosis in breast cancer

“…Loss of membranous syndecan‐1 expression had been shown to induce reduced cell adhesion, increased invasive potential, and dysregulated growth of mammary epithelial cells in vitro . The observed peritumoral and stromal CD138 staining could be a consequence of enzymatic cleavage of membrane‐bound CD138, which is then shed as soluble SDC1 (sSDC1) into the tumor environment …”

“…In normal tissues, CD138 is expressed on epithelial cells of various tissues and on plasma cells. Altered CD138 expression has previously been described in various malignant tumors . Overexpression of CD138 has been found in breast, gallbladder, urinary bladder, pancreatic, ovarian, endometrial, and prostate cancer .…”

“…Syndecan‐1 (CD138) is the first member of the four‐member syndecan family encoded by the SDC1 gene . It is built out of three structural domains from which one is an extracellular domain capable to bind heparin sulfates and chondroitin sulfates .…”

New strategies in achieving antiangiogenic effect: Multiplex inhibitors suppressing compensatory activations of RTKs

“…A new hypothesis emerged that various angiogenic RTKs associate and coordinate with each other to cooperatively induce an array of intracellular signaling cascades, instead of working individually . It was observed that there was an interplay between various RTKs for maintenance of endothelial junctions and vascular integrity during angiogenesis . In the midst of emerging resistance to the currently available antiangiogenic agents, future research should focus on developing multitarget antiangiogenic agents.…”

Proteoglycans in normal physiology and carcinogenesis

“…Совместно с другими поверхностными ГСПГ син-деканы могут быть вовлечены в поглощение экзосом, принимают участие в регуляции концентрации вну-триклеточного кальция и поддержании гомеостаза [15]. Интересно, что функция ПГ клеточной поверхности может быть изменена путем потери внеклеточного до-мена, что превращает связанные с мембраной коре-цепторы в молекулы, участвующие в паракринной регуляции [16].…”