Pancreatic cancer

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Desmoplastic Reaction in Pancreatic Cancer

Desmoplastic reaction has been proven to be a pathological hallmark of pancreatic cancer, and it reduces the prognosis significantly. The reaction leads to the creation of a conducive microenvironment that facilitates the spreading of the tumor. In so doing, the tumor grows at a more rapid rate and is able to metastasize (Feig et al., 2012). The delivery of chemotherapy also becomes ineffective in the sense that the desmoplastic reaction resists the mechanisms of action induced by chemotherapy. The desmoplastic reaction occurs as a result of compound pathways of molecular interactions which have been studied in attempts of developing novel targeted drugs (Nielsen, Mortensen & Detlefsen, 2016).

The molecular reasoning that defines desmoplastic reaction is when some dense and collagen-rich extracellular matrix forms around a pancreatic tumor. This characteristic goes hand in hand with an elevated proliferation of alpha-smooth muscle actin containing fibroblasts. With this alteration in the proliferation of stroma cells, not only does the pancreas change its heterogeneity but also changes in the pressure of the interstitial pressure occur. Stroma are produced when there is an increase in growth factors such as fibroblast growth factors, connective tissue growth factors, and epidermal cell growth factors (Nielsen, Mortensen & Detlefsen, 2016). The cancer cells become well-nourished in such an environment which makes to proliferate even more and metastasize. The treatment mechanisms that may be useful in the treatment of pancreatic tumors which elicit desmoplastic reaction should target these growth factors (Apte et al., 2004). For instance, small molecules that inhibit the enzyme tyrosine kinase have been found to be effective in the interference with the receptor of the epidermal growth factor. This strategy that targets desmoplastic reaction helps in the treatment of pancreatic tumors because it has been found to suppress fibroblast and satellite cell proliferation. Chemoresistance occurs during desmoplastic reaction because the reaction impedes effective drug delivery through the pancreatic duct (Whatcott et al., 2015). Therefore, the main molecules involved in the creation of the immunosuppressive microenvironment include the cancer-associated fibroblasts which are produced by the pancreatic stellate cells. The other molecules that lead to the formation of stroma in pancreatic cancer are the inflammatory cells, the endothelial cells, pericytes, and nerve cells (Nielsen, Mortensen & Detlefsen, 2016).

Clinical Trials on CAR T-cell Therapy

Clinical trials on T-cell therapy have involved the modification of the T-cells such that they recognize specific surface proteins on the cancerous cells. An example of antigens involved in pancreatic cancer pathogenesis that has been used in the generation of CAR T-cells is Mesothelin. Since Mesothelin is produced in pancreatic carcinoma, the ability to generate specific CAR T-cells that target it is a vital step in the therapeutic intervention.

The immunosuppressive tumor microenvironment in PDA interferes with the normal process of T-cell influx hence inducing a hypofunctioning state of the T-cells (Watanabe et al., 2010). However, with the generation of meso-CAR T cells in clinical trials, more efficacy has been proven in terms of recognizing tumor cells. In as much as these cells have been found to be more effective in recognizing cancer cell surface proteins, research is still ongoing to determine their maximum duration in the human body (Morgan et al., 2010).

More research in the production of CAR T-cells has been put into other cancers including myeloma, cervical cancer, lung cancer, and neuroblastoma (Lamers et al., 2013). Trials have also based their foundation on the expression of PSCA by cell lines from tumor cells. The in vitro activation of T- cells from a healthy donor and a patient using CD3 and CD28 leads to the generation of CAR T-cells that target PSCA (Katari et al., 2011). The initial trials on T-cell therapy focused mainly on blood cancers, and the saw researchers produce CAR T-cells that recognize a surface protein on the CD19 cell.

Most studies have also investigated the role of transmembrane mucins in tumor progression. For a long time, the recognition levels of mucins by the body’s immune cells have been low because their presumed role in the transmembrane mucous barrier. However, it has been discovered that mucins are overexpressed in human tumors as a strategy of effecting cell growth and survival. Therefore, prognosis from these malignancies greatly depends on the functional ability of mucins since they play a significant role in tumor progression. Mucin inhibitors have been developed to make them less effective in facilitating tumor progression.

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