Accumulation of Extracellular Hyaluronan by Hyaluronan Synthase 3 Promotes Tumor Growth and Modulates the Pancreatic Cancer Microenvironment

Abstract

Extensive accumulation of the glycosaminoglycan hyaluronan is found in pancreatic cancer. The role of hyaluronan synthases 2 and 3 (HAS2, 3) was investigated in pancreatic cancer growth and the tumor microenvironment. Overexpression of HAS3 increased hyaluronan synthesis in BxPC-3 pancreatic cancer cells. In vivo, overexpression of HAS3 led to faster growing xenograft tumors with abundant extracellular hyaluronan accumulation. Treatment with pegylated human recombinant hyaluronidase (PEGPH20) removed extracellular hyaluronan and dramatically decreased the growth rate of BxPC-3 HAS3 tumors compared to parental tumors. PEGPH20 had a weaker effect on HAS2-overexpressing tumors which grew more slowly and contained both extracellular and intracellular hyaluronan. Accumulation of hyaluronan was associated with loss of plasma membrane E-cadherin and accumulation of cytoplasmic β-catenin, suggesting disruption of adherens junctions. PEGPH20 decreased the amount of nuclear hypoxia-related proteins and induced translocation of E-cadherin and β-catenin to the plasma membrane. Translocation of E-cadherin was also seen in tumors from a transgenic mouse model of pancreatic cancer and in a human non-small cell lung cancer sample from a patient treated with PEGPH20. In conclusion, hyaluronan accumulation by HAS3 favors pancreatic cancer growth, at least in part by decreasing epithelial cell adhesion, and PEGPH20 inhibits these changes and suppresses tumor growth.

Breaking the Barrier—PEGylated Recombinant Human Hyaluronidase (PEGPH20)—A New Therapeutic Approach to the Treatment of Pancreatic Ductal Adenocarcinoma

“…[15][16][17] Increased HA also prevents chemotherapeutic agents and monoclonal antibodies from reaching their sites of action. 8,9 HA accumulation in the TME is associated with accelerated tumor growth and is an independent, negative predictor of survival.…”

“…7 Within the TME, hyaluronan (HA) is a naturally occurring linear polysaccharide, and a major component of the tumor stroma in many solid tumors, including PDA. 8 In animal models, accumulation of HA increases tumor interstitial fluid pressure (IFP), which in turn compresses blood vessels and compromises blood flow. [9][10][11][12] This process leads to hypoxia in the tumor, which is a contributory factor in metastasis.…”

175 The Ets-Transcription Factor Etv1 Regulates Stromal Expansion and Metastasis in Pancreatic Cancer

“…Has2 has been identified in vitro as significantly overexpressed in fibroblast coculture experiments with PDAC cells 39 and has been associated with significantly increased hyaluronic acid secretion. 40,41 Hyaluronic acid has been identified as a critical factor in the pancreatic tumor microenvironment that increases interstitial fluid pressure, collapsing potential vascular access to tumors. 10 PDAC xenografts utilizing over-expression of Has2 demonstrated increased tumor growth, loss of membranous E-cadherin and increased accumulation of cytoplasmic β-catenin.…”

“…10 PDAC xenografts utilizing over-expression of Has2 demonstrated increased tumor growth, loss of membranous E-cadherin and increased accumulation of cytoplasmic β-catenin. 41 Indeed, Has2 has been associated with poorer survival in human PDAC. 42 We found Etv1 overexpression was associated with Has2 increase by 4 fold ( Figure 5A).…”

Hyaluronan stimulates pancreatic cancer cell motility

“…In our previous study, we demonstrated overexpression and prognostic relevance of HA and its regulators in PDAC [17]. Recently, forced production and accumulation of extracellular HA by hyaluronan synthase (HAS) 3 overexpression have been shown to promote growth of PDAC tumor in mice [18]. These findings suggest the importance of HA in the progression of PDAC; however, only a few studies addressed its effects on the aggressive tumor phenotype, especially cell migration, in PDAC.…”