The role of hyaluronan in tumour neovascularization (review)

Abstract

Tumour growth and metastasis are totally dependant upon neovascularization. The target cell for tumour neovascularization is the blood-vessel endothelial cell, and specific angiogenic molecules produced or induced by the tumour are believed to initiate the process. In this report, we review one of these angiogenic molecules, the glycosaminoglycan hyaluronan (HA), which appears to have differing roles in neovascularization depending on its molecular mass. High-molecular-mass HA is anti-angiogenic whereas oligosaccharides of HA, of specific size, actively stimulate endothelial-cell proliferation and migration, 2 of the key events associated with neovascularization, and induce angiogenesis in vivo. We provide details of the action of HA oligosaccharides on endothelial cells, from binding to cell-surface receptors, through activation of signal transduction pathways and gene expression to protein synthesis, cell proliferation and cell migration. We also suggest a model to account for HA of differing molecular mass being present, at different locations, within a single tumour and how this HA aids both general tumour growth and tumour metastasis.

Expression of hyaluronan synthase 2 or hyaluronidase 1 differentially affect the growth rate of transplantable colon carcinoma cell tumors

“…These findings are consistent with previous observations of an anti-angiogenic effect of high molecular weight hyaluronan but an angiogenic effect of hyaluronan fragments. [45][46][47] Notably, Hyal1 in vitro requires an acidic pH for optimal activity. It is thus possible that close to neutral pH in tissues the secreted or cell surface associated Hyal1 activity 48 may induce only a limit degradation of hyaluronan, giving rise to angiogenic hyaluronan fragments.…”

“…49 Therefore, carcinoma cells that possess hyaluronidase activity may be surrounded by hyaluronan fragments that induce differentiation of endothelial cells. 47,50 The mechanism behind the tumor promoting effect of hyaluronan remains to be elucidated. It is possible that hyaluronan chains of high molecular mass, which are known to cause tissue expansion, facilitates nutrient flow in tissues.…”

Testicular hyaluronidase induces tubular structures of endothelial cells grown in three‐dimensional colagen gel through a CD44‐mediated mechanism

“…5,13,14 An important question is whether hyaluronidase induces endothelial cell tube formation through the formation of hyaluronan fragments with angiogenic activity or through another yet unknown mechanism. If the mechanism involves production of hyaluronan fragments, hyaluronan needs to be present in the assay.…”

“…11,12 In angiogenesis, hyaluronan plays a dual role; native high molecular weight hyaluronan prevents it, whereas hyaluronidase-degraded hyaluronan (fragments of 6 -20 saccharides) induces formation of new blood vessels in chicken chorioallantoic membrane. 5,13 We also observed that hyaluronan dodecasaccharides induced endothelial cells grown in a 3-dimensional (3D) collagen gel to form tubular structures, in a process not mediated through activation of FGF receptors. 14 These results are in conformity with those of Montesano and his colleagues, 15 who found that hyaluronan fragments acted synergistically with VEGF, but not with bFGF, in the induction of endothelial cell tube formation.…”

“…ECM compounds that mediate angiogenesis are native collagen gels, fibrin, proteoglycans, glycosaminoglycans and matrix-degrading enzymes. [3][4][5][6] Hyaluronan is a glycosaminoglycan found in virtually every tissue in vertebrates. It is synthesized by membrane-associated hyaluronan synthases 7,8 and is degraded by hyaluronidases.…”