Revisiting stroma in pancreatic cancer

Clinically, pancreatic tumors have proven to develop resistance to available treatment options; however, efficacy might be achieved if the required levels of drugs reach the tumor site. Tumor microenvironment (TME) leads to extensive desmoplasia and chemo-resistance, contributing immensely to the invasive and metastatic process of pancreatic carcinoma [1]. Desmoplasia involves the excessive production of extracellular matrix and is associated with proliferation of stromal cells, including myofibroblasts and stellate cells. Recent studies suggest that the Sonic hedgehog (SHH) pathway plays a key role in desmoplasia [2] and progression of cancer, including pancreatic ductal adenocarcinoma (PDAC) [3, 4]. The implementation of stromal targeting strategies in clinical practice still poses significant challenges due to vast heterogeneity in sensitivity across different cancers and even tumor types. This may be likely due to inherent differences in expression of pro-angiogenic, invasiveness factors, growth factors/receptors and differential dependency of tumors on hypoxia and nutrition. Unlike other tumor types, pancreatic tumors that are surrounded by abundant stroma have hypo-vascularity and poor perfusion that render them less dependent on vascular supply, leading to tumor growth and hindrance in drug delivery [5]. However, so far, preclinical/clinical data reveal that despite most of the hedgehog pathway inhibitors could deplete the pancreatic tumor stroma, the outcomes outweighed over the therapeutic benefit. One plausible explanation could be the result of the side effects other than the diminution of stroma. Therefore, the identification of novel modalities that could target pancreatic stroma and overcome inaccessibility of drugs is desired. Our study, published in Cancer Research [6], provides a preclinical proof of concept suggesting that ormeloxifene, a non-steroidal, might improve therapeutic outcomes in pancreatic cancer by targeting the stromal component. This study reinforces an insight that pancreatic Editorial