Versican: Role in Cancer Tumorigenesis

Versican—A Critical Extracellular Matrix Regulator of Immunity and Inflammation

“…Tumor cell-derived versican in turn promotes accumulation and secretion of proinflammatory TNFα and IL-6. In addition, we found significantly elevated expression and accumulation of versican in leiomyosarcoma (LMS), a metastatic uterine cancer, when compared to the more benign leiomyomas and control healthy tissue (103,168). Importantly, cultured human LMS cells synthesized large quantities of versican, forming extensive pericellular coats around the tumor cells.…”

“…Versican is essential during development (76,77) and it is now becoming apparent that it is an important component of the tissue inflammation caused by infection and tissue injury (10). Versican accumulates as part of the early inflammatory response in a number of human diseases often associated with the invasion of leukocytes including those in the vascular system (10,40,(78)(79)(80)(81)(82)(83)(84), lung (5,6,60,77,(85)(86)(87)(88)(89), brain and spinal cord (53,(90)(91)(92), intestine (93)(94)(95)(96), heart (97), liver (63), skin (98,99), eye (100, 101), pancreatic islets (102), and many different forms of cancer [reviewed in (103)(104)(105)]. The accumulation of versican in these tissues is usually associated with other ECM components that bind versican, such as hyaluronan (106,107), link protein, TSG-6, IαI, and CD44 (95, 96, 108-111) (Figure 1).…”

“…Versican is a central player in cancer development in that it impacts tumor-promoting inflammation, immune surveillance evasion, and immunomodulation (164). Versican expression increases as part of the inflammatory response in a number of cancers [reviewed in (22,103,105,165)]. In both breast cancer and Lewis lung carcinoma, the presence of versican produced by the tumor cells leads to an accumulation and activation of tumor-associated macrophages (TAMs) via TLR2 and its co-receptors TLR6 and CD14 (118,119,159,(165)(166)(167).…”

“…Importantly, cultured human LMS cells synthesized large quantities of versican, forming extensive pericellular coats around the tumor cells. Blocking versican synthesis with siRNA to versican reduced the thickness of the cell coats and inhibited their proliferation and migration in vitro and tumor formation in vivo (103,168).…”

“…Infiltrating myeloid cells secrete versican which can also exhibit immunosuppressive activities in some cancers (74,75,103,118,184,185). For example, ADAMTS-generated versikine regulates mouse BATF3-dendritic cell (BATF3-DC) differentiation (74).…”