Researcher: Dr. Jomnarong Lertsuwan

1. Purinergic Signaling in Cholangiocarcinoma

    New therapeutic strategies and novel compounds for Cholangiocarcinoma (CCA) treatment are being sought. One of the emerging therapeutic agents for cancer is ATP. ATP signals through a subfamily of purinergic receptors known as P2Y and P2X receptors. Also, ATP could be hydrolyzed into adenosine and signal through adenosine receptors. Effects of ATP and adenosine on cancers vary depending on the cancer type, potentially due to the differential expression of purinergic receptors on each cancer type, and the dosage of extracellular ATP or adenosine used (8-10). Short- and long-term (trophic) purinergic signaling in humans has been studied in both normal and pathogenic conditions, including in cancers. Some researchers have suggested the variable responses of cancer cells to extracellular nucleotides. Extracellular ATP inhibited growth and motility of nasopharyngeal carcinoma cells by inducing apoptosis through P2Y2 receptor. P2X7, as one of the ATP receptors, was shown to mediate pyroptosis from cytosolic LPS and a catalytic activity of caspase-11. In addition, P2X7 receptor was shown to be a critical player in antitumor immune responses in mice. Tumor growth and metastatic spreading were accelerated strongly in mice lacking the P2X7 receptor. Nevertheless, high dose of ATP induced cell death through P2X7 and AMPK/mTOR signaling in colon cancer cells. In addition, P2X7 receptor is required to mediate cell death in lung cancer cells.

Current researches
1) Inhibitory Effect of ATP and Adenosine on Cholangiocarcinoma Cell Proliferation, Motility, Autophagy, and Cell Death
2) Receptor Independent Mechanism of Adenosine in Cholangiocarcinoma

 2. Inflammation and Cholangiocarcinoma disease development and progression

    Cholangiocarcinoma (CCA) is a lethal cancer of bile duct epithelia, which usually coexists with chronic inflammation of liver and bile ducts. The incidence of CCA has been gradually increasing worldwide during the last two decades, particularly in the northeastern provinces of Thailand, where the incidence as high as 115 per 100,000 in males was observed. Risk factors for CCA commonly lead to chronic inflammation of liver, liver damage, or inflammatory injury of the bile ducts. The risk factors include but not limit to hepatolithiasis, primary sclerosing cholangitis (PSC), parasitic infection (Opisthorchis viverrini or Clonorchis sinensis), fibropolycystic liver disease, Hepatitis B and/or C virus infection, and chemical carcinogens exposure. Some compounds that reduce inflammation has been shown to inhibit CCA growth.

    Furthermore, kinin system was shown to mediate both chronic and acute inflammation. Bradykinin receptors were overexpressed in many types of cancers especially cancers of urogenital system and digestive track and was recently used in preclinical cancer imaging. Activation of bradykinin receptor B₁ and B₂ was reported to upregulate NF-κB level and leading to a release of cytokines and an activation of NO, MAPK, RAS, and angiogenesis pathways. B1R is a receptor mainly found upregulated in cancer cells while B2R is a house keeping receptors for inflammation. Recent review by da Costa et al presented that many cancer cells express overexpressed level of B1R and the autocrine activation was observed in some cancers.

Current researches
1) Inflammation and Cholangiocarcinoma Disease Development and Progression
2) Kinin system and Inflammation in Cholangiocarcinoma