By controlling bacterial infection causing typhoid fever could dramatically reduce the risk of gallbladder cancer in India and Pakistan. A study conducted by researchers of the Institute of Medical Sciences, Banaras Hindu University (BHU) and the Netherland Cancer Institute, was published in CELL HOST & Microbe journal on Thursday. The study was done by Gopal Nath of the department of Microbiology, Institute of Medical Sciences, and Jacques and Neefjes Tiziana Scanu of Netherlands Cancer Institute.

According to Nath, the findings establish for the first time the causal link between bacterial infection and gall bladder cancer, explaining why this type of cancer is rare in the West but common in Indian subcontinent where typhoid fever is endemic. Public policy changes inspired by this research could have an immediate impact on preventing a type of cancer that currently has a very poor prognosis. While viruses are among the established causal factors for particular cancers, bacteria are largely ignored as direct contributors. Accepting that bacterial infections can directly contribute to cancer formation makes these tumors preventable in principle. If Salmonella Typhi infections are cured immediately antibiotics and chronic infection are prevented or cured by some means or if vaccination programme to eradicate S. Typhi work, a major reduction is expected in the incidence of a tumor that represents the third commonest gastrointestinal tumor in India and Pakistan.

Gall bladder cancer is hard to diagnose in its early stages because there are no signs or symptoms. By the time cancer is detected, it is often too late to save the patients. Professor VK Shukla, a gastrointestinal surgeon, said that usual survival period of such patients hardly exceeds 6 months after the detection. Because the prognosis is so poor, the researchers set out to gain insight into how to combat this tumor by identifying causal factors underlying its unique global distribution. They zeroed in on S. Typhi because this — causing bacterium is endemic in India and have been associated with gallbladder cancer in many of epidemiological studies including one which was published by Gopal Nath and his research group in 2008. Moreover, proteins that Salmonella injects into host cells activate cancer related signaling pathways called AKT and MAPK, which support not only bacterial infection and survival but also the growth and proliferation of cancer cells.

According to them, to explore the role of S. Typhi in cancer in the new study, Neefjes and Scanu compared tumor samples from Indian and Dutch patients with gall bladder cancer. While both group showed signs of AKT and MAPK activation and an inactive TP53 cancer gene, only Indian patients showed strong evidence of S. Typhi infection and over activating mutation in cancer gene c-Myc. To mimic the features of tumor samples from India, the researchers transplanted Salmonella- infected cells with mutations affecting TP53 and c- Myc activity in mice. These mice latter developed tumors, demonstrating that Salmonella causes cancer in genetically at-risk host as a result of the collateral damage induced by its normal infection cycle.

Additional experiments suggested that Salmonella infection sets genetically predisposed host cells on the cancerous path by secreting proteins that increase AKT and MAPK activity, which remains elevated and perpetuates the cancer trajectory long after the bacteria have disappeared. These same two host signaling pathways are activated by bacterial pathogens implicated in cervical and lung cancer, suggesting that a direct contribution of bacteria to tumor formation could be more common than previously anticipated. The findings also suggest that the use of antibiotic treatment to control these bacterial infections may come too late for individuals who have already developed cancer. Instead, the main goal should be prevention through proper treatment with different antibacterial modalities, vaccination program and better sanitary conditions.

In future studies, the researcher will investigate whether Salmonella contributes to tumors in other tissues, identify other cancer causing bacteria, and determine how these pathogens leave an imprint of infection in host cells. “Our findings may now be used to urge policy makers to take appropriate measures to eliminate or better control these infections,” Dr Nath says adding, “If typhoid fever is controlled, gallbladder carcinoma in Indian subcontinent could be prevented and become as rare as in the Western world”.