Pancreatic ductal adenocarcinoma

Pancreatic stellate cells (PSCs) mainly distributed around the pancreatic glands that are able to synthesize matrix proteins, matrix metalloproteinases (MMP), and MMP inhibitors that regulate ECM turnover. PSCs can be activated by factors including pro-inflammatory cytokines, oxidant stress, and by factors of particular interest in PDAC such as hypoxia, hyperglycemia, and increased interstitial pressure. The activated PSCs can secrete various growth factors to promote the growth and proliferation of pancreatic cancer cells, inhibit their apoptosis, and enhance their invasion ability. PSCs have been confirmed to be the predominant source of collagen in the tumor stroma, and able to secrete ECM proteins like α-smooth muscle actin and collagen. An investigation that specifically decreases myofibroblasts and ECM in PDAC in vivo can inhibit tumor growth and enhance the sensitivity of chemotherapy drugs. Some clinical trials targeting ECM and stroma have been investigated, in which hyaluronidase has been considered as a therapeutic breakthrough. A multi-pronged approach aimed at tumor cells as well as stromal elements may be the key to achieve better clinical outcomes in PDAC patients.

Activated fibroblasts in the TME are called CAFs and are one of the most predominant cell types found in the stroma with several functional subtypes. Due to the heterogeneity in each subgroup, it is difficult to regulate the TME by targeting fibroblasts.¹² Myofibroblastic CAFs (myCAFs) and inflammatory CAFs (iCAFs) are the most common CAFs in PDAC, and a new population of CAFs that defined as antigen-presenting CAFs (apCAFs) was recognized via single-cell RNA sequencing. myCAFs are distributed around acinus and express alpha-SMA, while iCAFs located more distantly from neoplastic cells, which lacked elevated αSMA expression and instead secreted interleukin (IL)-6 and additional inflammatory mediators. apCAFs express MHC class II and CD74, but do not express classical co-stimulatory molecules. They can activate CD4+ T cells in an antigen-specific fashion in a model system, confirming their putative immune-modulatory capacity. Interestingly, some CAFs are tumor promotive while some CAFs are tumor inhibitive. For example, iCAFs can secrete ECM and cytokines like IL-6, IL-11, and leukemia inhibitors. These cytokines can activate IL-6R positive malignant cells and myeloid cells to subsequentially activate the STAT-3 signaling pathways to promote tumor growth. In a mouse model, the IL-6R targeted treatment reduced the activation of STAT-3 pathways and enhanced the antitumor response to chemotherapy, suggesting that the IL-6 pathways may be potential therapeutic targets.CAFs can produce tryptophan decomposition enzymes, like indoleamine 2, 3-dioxygenase and arginase, both of which can enhance the function of immunosuppressive macrophages and inhibit Tregs.In addition, CAFs are reported to significantly increase the release of exosomes when exposed to chemotherapy like gemcitabine, and these exosomes increased chemoresistance-inducing factor in recipient epithelial cells and promote proliferation and drug resistance. However, Ozdemir et al demonstrated that complete depletion of tumor stroma by targeting CAFs accelerated the progression of PDAC with reduced overall survival, underscoring the highly complex nature of tumor stroma. It seems that targeting the pancreatic tumor stroma does not simply require complete ablation, but needs to be carefully modulated.

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Pancreatic Disorder and Therapy