A lipid against pancreatic cancer: Reprogramming the tumor stroma

Significance

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.

 

A lipid against pancreatic cancer: Reprogramming the tumor stroma-Medicine Innovates

About the author

Jai Prakash obtained his MSc (Pharmacology) from All India Institute of Medical Sciences, New Delhi, India and then PhD (cum laude) from the University of Groningen. Thereafter, he worked as a Vice President – Preclinical Research at BiOrion Technologies with a joint position at the University of Groningen. He developed novel technologies to inhibit fibrosis, which are currently in the pipeline of BiOrion. After few years, he joined Karolinska Institutet, Stockholm, Sweden and worked on identification of novel targets in tumor stroma. He received prestigious funding from Swedish Cancer Foundation grant, European Commission (Marie Curie Career Integration Grant) and Young Researcher Swedish Research Council Project grant to develop new targeted nanotherapeutics against cancer. About 6 years ago, he started his own research line at the University of Twente as a Tenure-track Assistant Professor. He is currently Adjunct Professor and heading the research group “Targeted Therapeutics”.

His research is focused on the development of novel targeting technologies to modulate the tumor microenvironment to treat cancer. His team has developed novel peptide therapeutics and targeting nanosystems to modulate the tumor microenvironment which have resulted in two key patents and several high impact publications. In 2016, he founded a spin-off company ScarTec Therapeutics BV., which aims to develop novel peptide-based technologies for inhibiting scar formation and improve the effect of chemotherapy in pancreatic cancer. He holds a position of Managing Director in the company. ScarTec has successfully obtained Take-off phase-2 valorization funding from the Dutch Research Organization and European Commission SME phase-I to support further product developments. At the academic level, he has served as a main theme editor for several journals including Advanced Drug Delivery Reviews and Frontiers in Oncology. He has been a reviewer for reputed journals from different fields such as Science Translational Medicine, PLoS Pathology, Nanoletters, Journal of Controlled Release. He has also been a reviewer and panel member for international grant agencies including EPSRC UK, Israel Science Foundation, Israel Ministry of Science, Technology and Space, Agence Nationale Recherche France, etc.

Reference

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

Go To Cancer Letters 420

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