Pancreatic ductal adenocarcinoma is the most common malignancy of the pancreas. Although radiotherapy and cytotoxic chemotherapy are considered as the golden standard for treatment, they provide patients with little survival benefit of just few months. The current 5 years survival rate for this cancer is only 7%. The low efficacy of these treatments has been attributed to the abundant growth of fibrous or connective tissue (a.k.a. desmoplasia), which is commonly known as tumor stroma. Tumor stroma is mainly comprised of cancer-associated fibroblasts (CAFs); the major precursors of CAFs are the human pancreatic stellate cells (hPSCs) which habitat within the normal pancreas. In the case of pancreatic ductal adenocarcinoma, the quiescent hPSCs proliferate enormously and secrete large amounts of fibrous extracellular matrix (ECM) proteins. In addition, they also secrete growth factors and cytokines that stimulate tumor progression.
Recently, University of Twente scientists: Jonas Schnittert, Marcel Heinrich, Praneeth Kuninty, Gert Storm and led by Professor Jai Prakash from the Targeted Therapeutics group have found an endogenous lipid lipoxin-A4 which is secreted in very low amounts by immune cells during inflammation, can be used to control hPSC-induced tumor-promoting activities. Although few studies have reported the anti-fibrotic and inhibitory effects of LXA4 in different animal models, there is a dearth of information on the impact of LXA4 on the differentiation of hPSCs and the growth/ progression of pancreatic tumors. They demonstrated the inhibitory effects of LXA4 on the activation and migration of hPSC, as well as its impact on the progression and growth of pancreatic cancer cells. The research work is published in Cancer Letters.
The authors observed that LXA4 treatment significantly inhibited the change in morphology and expression of α-SMA and Col1 proteins in a concentration-dependent manner. It also inhibited the expression of TGF-β-induced genes that code for CAF phenotypes, growth factors, cytokines that induce tumor growth, membrane receptors, enzymes that facilitate altered ECM composition and turnover (MMP2), genes involved in homeostasis and cholesterol production, intracellular proteins and ECM proteins.
The research team found that TGF-β activates the phosphorylation and translocation of Smad 2/3 pathway into the nucleus. However, LXA4 treatment inhibited the phosphorylation and translocation of Smad 2/3 pathway into the nucleus. In addition, the incubation of Panc-1-cells with the conditioned media from TGF-β-activated hPSCs induced cell growth and migration compared to the conditioned media of non-activated hPSCs, while the treatment of the conditioned medium with LXA4 reduced cell growth and migration. Also, LXA4 treatment of hPSCs before spheroid formation resulted in a significant reduction of spheroid size compared to spheroids formed from ethanol (solvent)-treated hPSCs. Additionally, the spheroids formed from LXA4 treated hPSCs expressed lower levels of Col-1 proteins compared to ethanol-treated hPSCs.
Moreover, the authors observed that the newly formed areas of proliferation on the cell surfaces of control-treated spheroids were not seen in LXA4-treated spheroids. Importantly, treatment with LXA4 inhibited the growth of 3D spheroids comprised of both tumor cells and hPSCs but not of spheroids formed with only tumor cells. This indicated that the effect of LXA4 is exerted through the inhibition of hPSC-driven tumor cell proliferation. Intriguingly, the intraperitoneal and intratumoral injections of LXA4 significantly inhibited the tumor growth and the effects were attributed to the reduced desmoplasia in tumors.
The novel study by Professor Jai Prakash and colleagues provide compelling evidence that the endogenous lipid LXA4 attenuates tumor growth through the inhibition of PSC-induced desmoplasia in pancreatic tumors, the reversal of hPSC activation into CAF and the modulation of hPSC-induced tumor-promoting effects. Their findings will advance further studies on the evaluation of LXA4 as a potential candidate for the reprogramming of tumor stroma and treatment of pancreatic ductal adenocarcinoma.
Schnittert, J., Heinrich, M.A., Kuninty, P.R., Storm, G., and Prakash, J. Reprogramming Tumor Stroma Using an Endogenous Lipid Lipoxin A4 to Treat Pancreatic Cancer, Cancer Letters 420 (2018) 247-258