Role of hyaluronan synthesis for tumor-host interactions and progression of esophageal squamous neoplasms

• Applicant: Professor Dr. Jens W. Fischer
• Subject Area: Pharmacology
• Term: from 2010 to 2015
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 174386703

• Final Report Year: 2015

Final Report Abstract

For esophageal and bladder cancer, hyaluronan (HA) and stromal ECM are thought to play an important role for pathophysiology and clinical outcome. HA is a polymer of alternating Nacetylglucosamine and glucuronic acid residues and is one of the main carbohydrate components of the extracellular matrix (ECM). HA is synthesized by three HA-synthase (HAS) isoenzymes (HAS1, HAS2, HAS3) and signals via HA-receptors RHAMM and CD44. Analysis of extracellular matrix gene expression revealed in bladder cancer that RHAMM, HAS3 and the proteoglycan biglycan were differentially regulated during tumor progression. Further analysis revealed that RHAMM was positively correlated with tumor specific mortality, whereas high biglycan expression was negatively correlated to tumor specific mortality. Detailed in vitro and in vivo analysis revealed that RHAMM indeed increases tumor cell proliferation and xenograft tumor growth whereas biglycan was a negative regulator of these parameters. Furthermore, biglycan was upregulated by tyrosine kinase inhibitors suggesting that induction of biglycan rich microenvironment could contribute to the anti-tumor effects of these agents. Furthermore a synergistic inhibition of esophageal cancer cell (ESCC) growth was demonstrated if the synthesis of HA and the EGF signalling were simultaneously inhibited by 4-MU and erlotinib. HA is important for shaping the microenvironment of tumors. Here it is shown that direct contact between ESCC and fibroblast induce HA-synthesis and chemokine expression by stromal fibroblast, thereby providing a new facette of the role of stromal HA and the mechanisms of regulation. In this case Wnt-signalling appeared to be primarily mediating the induction of HAS2 expression in fibroblasts. Taken together, this project revealed a role of RHAMM and biglycan in bladder cancer and suggest the expression of these molecules as new prognostic markers of disease progression and survival. Furthermore EGF- and HA-signalling synergistically support ESCC growth which may be considered as a new therapeutic strategy to enhance response rates by simultaneously affecting tumor cell signalling and the stromal microenvironment. This appears promising because the HA-rich microenvironment is shown here to be directly regulated by tumor cell-fibroblast interactions.

Publications

• Inhibitory role of the small leucine-rich proteoglycan biglycan in bladder cancer. PLoS One, 2013. 8(11): p. e80084
  Niedworok C., Röck K., Kretschmer I., Freudenberger T., Nagy N,. Szarvas T., Vom Dorp F., Reis H., Rübben H., Fischer JW
  
• The impact of the receptor of hyaluronan-mediated motility (RHAMM) on human urothelial transitional cell cancer of the bladder. PLoS One, 2013. 8(9): p. e75681
  Niedworok C., Kretschmer I., Röck K., Vom Dorp F., Szarvas T., Heß T., Freudenberger T., Melchior- Becker A., Rübben H., Fischer JW
  
• Synergistic effect of targeting epidermal growth factor receptor and hyaluronan synthesis in esophageal squamous cell carcinoma cells. British Journal of Pharmacology, Volume 172, Issue 18, September 2015, Pages 4560-4574
  Kretschmer I., Freudenberger T., Twarock S., Fischer JW
  
• Esophageal squamous cell carcinoma cells modulate chemokine expression and hyaluronan synthesis in fibroblasts, 2016, 291, 4091-4106
  Kretschmer I., Freudenberger T., Grandoch M., Yamaguchi Y., Fischer JW