Recent advances in multimodal treatment, including surgery, chemotherapy, radiotherapy, and immunotherapy, have contributed to the improvement of treatment results for various gastroenterological malignancies. However, the prognosis of pancreatic adenocarcinoma (PDAC) remains extremely poor, with a 5‐year survival rate of <10%. Aggressive biological features of early remote metastasis and local invasiveness, no method for early detection or sensitive biomarkers, and resistance to chemotherapy are all implicated as factors responsible for the dismal prognosis. Furthermore, molecular‐targeting agents that are effective for other gastroenterological cancers have been proven invalid for PDAC in most clinical trials.
Recent studies have shown that the stroma of PDAC creates a microenvironment for the tumor to evade the host immune system and drug delivery, leading to rapid cancer progression and resistance to chemotherapy. In the current issue, Murakami et al1 reviewed the role of the tumor microenvironment in pancreatic cancer from the perspective of each stromal component, especially immune cells.
Pancreatic adenocarcinoma has the unique characteristic of being associated with the presence of dense fibrous tissue, which is known as desmoplastic stroma. The stroma consists of cancer‐associated fibroblasts (CAFs), endothelial cells, various kinds of immune cells, and extracellular matrix. CAFs, which are the major cellular component of pancreatic cancer stroma, secrete various components of the extracellular matrix, such as collagen, proteoglycan, fibronectin, integrin, matrix metalloprotease, secreted protein acidic and rich in cysteine, and glycosaminoglycans including hyaluronic acid. The fibrous stroma increases the mechanical pressure of the tumor, which may inhibit the intratumoral shift of the immune cells and drug delivery.
Cancer‐associated fibroblasts also play a pivotal role in inducing epithelial‐to‐mesenchymal transition, angiogenesis, cancer invasion, and metastasis through activation by transforming growth factor β excreted from the pancreatic cancer and the stroma itself. Regulatory T cells, myeloid‐derived suppressor cells, and tumor‐associated macrophages are all involved in cancer progression through the creation of the immunosuppressive microenvironment for PDAC.
Therefore, cancer stroma‐targeting therapy appears to represent a new promising strategy in the treatment of PDAC. Depletion of the desmoplastic stroma, including CAF and each component of the extracellular matrix, may lead to the suppression of cancer progression by regulating the immune response in the tumor microenvironment and improving drug delivery to PDAC cells. However, several challenges have been encountered in attempts to reduce the volume or modulate the function of the desmoplastic stroma in pancreatic cancer.
Combination chemotherapy of nab‐paclitaxel plus gemcitabine has been shown to induce marked tumor shrinkage and prolong the overall survival in patients with metastatic PDAC in an international, multicenter, open‐label, randomized phase III study (the MPACT trial).2 In a similar phase II trial of Japanese patients, a waterfall plot analysis showed marked volume reduction at both the primary and metastatic sites. In the preclinical study, the depletion of CAF with amorphous changes in collagenous fibers and an increase in the gemcitabine level in cancer cells were observed.3
The dense stroma of PDAC is characterized by excess accumulation of hyaluronic acid, which inhibits the migration of immune cells and their contact with cancer cells. Drug delivery is also blocked through elevation of intratumoral mechanical pressure. In addition, hyaluronic acid functions as a ligand for CD44, which is a stem cell marker related to cancer cell growth.4
Given that pegvorhyaluronidase alfa (PEGPH20), a pegylated recombinant human hyaluronidase, degrades intratumoral hyaluronic acids and remodels the tumor stroma, the HALO‐202 trial was designed as a phase II study.5 Patients with previously untreated metastatic PDAC were randomly assigned to treatment with nabpaclitaxel and gemcitabine plus or minus PEGPH20. The study met its primary endpoints of progression‐free survival (PFS) and occurrence of thrombotic adverse events. PFS was significantly improved overall and for patients with hyaluronic acid‐rich tumors. A global phase III study is currently ongoing in patients with hyaluronic acid‐rich PDAC.
Thus, cancer stroma‐targeting therapy has the potential to modulate the microenvironment of PDAC. This new approach may become a new treatment modality in addition to surgery, chemotherapy, radiotherapy, and immunotherapy for managing refractory cancer with desmoplasia.
DISCLOSURE
Conflicts of Interest: Author declares no conflicts of interest for this article.
REFERENCES
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