More than a Gel & Hyaluronic Acid, a Central Component in the Microenvironment of Pancreatic Cancer

Abstract

Hyaluronic acid or hyaluronan (HA) is a major stromal component and its accumulation has been shown to play a central role in promoting tumourigenesis and progression of disease. Thus, overexpression of HA in tumours is associated with poor prognosis. Therapeutic targeting of HA is therefore an attractive strategy, particularly in pancreatic ductal adenocarcinoma (PDA), which is associated with an extremely poor prognosis and less sensitivity towards chemotherapy. PDA is characterised by a high stromal content. The accumulation of dense, fibrotic extracellular matrix components within the stroma, termed desmoplasia, results in increased tumour interstitial fluid pressure and vascular compression that impair the delivery and efficacy of therapeutic agents. While some elements of the stroma may be protective for the patient and prevent a more aggressive phenotype of PDA, a pegylated recombinant human hyaluronidase (pegvorhyaluronidase alfa) has been found to inhibit tumour growth in preclinical studies. In a clinical phase II randomised trial, the addition of pegvorhyaluronidase alfa to nab-paclitaxel and gemcitabine suggested significantly longer progression-free survival in patients with advanced PDA compared with nab-paclitaxel and gemcitabine alone. This benefit was even more pronounced in a subgroup of patients who expressed high levels of tumour HA.

Programmable Living Units for Emulating Pancreatic Tumor‐Stroma Interplay

“…[35] Increasing evidences have suggested that HA, a negatively charged nonsulfated glycosaminoglycan, is abundantly accumulated in tumor surrounding stroma, contributing to an extensive desmoplastic reaction. [36,37] Although the process by which HA accumulated in PDAC stroma is still under investigation, recent proteomic and genomic-based evidences have demonstrated that while both cancer cells and CAFs produce increasing levels of collagens, it was verified that HA is mostly overexpressed by CAFs and it is highly concentrated in the stromal region. [26,36,38] Interestingly, owing to HA role in fibrotic stroma establishment and in hampering anticancer drugs delivery, efforts are being focused on targeting this stroma component by administration of HA-targeting enzymatic agents.…”

Oncolytic Virotherapy: A New Paradigm in Cancer Immunotherapy

“…In squamous carcinomas of the head, neck, and skin, the hyaluronan levels are decreased and relate to the neoplasia stage [182]. Increased concentrations are associated with aggressive neoplasms and poor prognoses [184]. Hyaluronidase degrades the ECM and decreases interstitial fluid pressure.…”

Targeting the Stroma in the Management of Pancreatic Cancer

“…Targeting HA deposition can be divided into 3 approaches: depleting stromal HA, inhibiting HA synthesis, and blocking HA signalling (79). In a mouse model, pegvorhyaluronidase alfa (PEGPH20), the PEGylated form of a recombinant human hyaluronidase, has been shown to deplete or reduce HA within the stroma, thereby improving tumour perfusion and drug delivery (80).…”