Key Link Responsible For Colon Cancer Initiation, Metastasis

For instance, more than 20 percent of patients with a form of inflammatory bowel disease (IBD) develop colorectal cancer within 30 years of diagnosis. This colitis-associated cancer has a slow progression, but a very poor response to treatment and a high mortality rate. Researchers have known that the broad mechanisms of cancer involve an interplay with the immune system response that includes: recruiting immune cells that influence the tumor microenvironment, escaping from host immunosurveillance and suppression, shifting of the host immune response, and tumor-associated angiogenesis to establish the blood supply. For the study, the research team first “knocked-out” or removed the CXCR2 gene in mice, and found that the signs typically associated with inflammation were prevented. Furthermore, they demonstrated that CXCR2 dramatically suppressed colonic inflammation and the colitis associated tumor formation, growth and progression in mice. CXCR2 decorates the outer part of immune cells called myeloid-derived suppressor cells, or MDSCs, that work to block the immune response of killer CD8+ T cells. In the knockout mice, without CXCR2 present, the MDSC cells could no longer migrate from the circulatory system to the colon, dodge the killer CD8+ T cell immune response, and feed the blood supply of the tumor environment. Furthermore, when they transplanted normal MDSC cells (with normal CXCR2) into the knockout mice, tumor formation was restored. “These results provide the first genetic evidence that CXCR2 is required for recruitment of MDSCs into inflamed colonic mucosa and colitis-associated tumors,” said DuBois. For DuBois, who has devoted his career to unraveling the inflammatory circuitry responsible for colon cancer, the results help connect the dots between the immune system, inflammation and tumor formation and metastasis. DuBois’ team was the first to show that colorectal tumors contained high levels of the enzyme cyclo-oxygenase-2 (COX-2), a key step in the production of pro-inflammatory mediators such as prostaglandin E2 (PGE2). PGE2 triggers production of a CXCR2 molecule that fits into CXCR2 like a baseball into a glove’s pocket and activates it. CXCR2, like the pied piper, recruits MDSCs from the bloodstream to sites of inflammation, causing the colon cancer tumors to evade the immune killer CD8+ T immune response. “Our findings reveal not only how MDSCs are recruited to local inflamed tissues and tumor microenvironment and how local MDSCs contribute to colorectal cancer progression, but now also provide a rationale for developing new therapeutic approaches to subvert chronic inflammation- and tumor-induced immunosuppression by using CXCR2 antagonists and neutralizing antibodies,” said DuBois. Story Source: The above story is based on materials provided by Arizona State University . Note: Materials may be edited for content and length.

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Treating Unresectable Metastatic Colorectal Cancer

A systematic review showed that approximately 50% of salvage patients have an overall survival of more than 12 months after this nuclear medicine therapy. Colorectal cancer is the third most commonly diagnosed type of cancer worldwide in men and the second in women, and it is also the third most common cause of death. In approximately 50% of patients, metastases to the liver are present at diagnosis or during follow-up, which account for a large portion of morbidity and mortality in patients. A structured review was performed by researchers to gather all available evidence on radioembolization for the specific group of patients with colorectal cancer liver metastases. “Although quite some reviews are printed on the subject of radioembolization, we felt that a structured and comprehensive review on survival and response data for these patients was lacking,” said lead author Charlotte E.N.M. Rosenbaum, PhD, of University Medical Center Urecht in The Netherlands. The study was published in the November issue of The Journal of Nuclear Medicine (2013; doi:10.2967/jnumed.113.119545). The research team reviewed a total of 13 articles on Y-90 radioembolization as a monotherapy and 13 articles on Y-90 radioembolization as a combined with chemotherapy. Among the studies, disease control rates (ie, complete response, partial response, and stable disease) ranged from 29% to 90% in the monotherapy studies, which involved 901 patients. In the studies in which Y-90 radioembolization was combined with chemotherapy, involving 472 patients, disease control rates ranged from 59% to 100%. “From the studies included in this systematic review, survival proportions of approximately 50% were found. Therefore, in this group of salvage colorectal cancer liver metastases patients who otherwise have no regular treatment options and a life expectancy of less than 6 months, Y-90 radioembolization seems to be a hopeful treatment option,” noted Rosenbaum. “Our paper shows all published data on this subject from the first randomized trial onwards. Furthermore, we have determined 12-month survival proportions for all included articles to provide a better overview and to better allow for comparisons. Finally, this overview of the literature shows which topics have not been the focus of much research and may thus be interesting for further work.” Similar Articles

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Nuclear medicine improves survival from colorectal cancer metastasis to the liver

Looking more closely at location, moderator John L. Marshall, MD, poises the question of selecting treatment for patients with KRAS G13D mutations. Johanna Bendell, MD, explains that recent findings contradict the initial pooled analysis of the CRYSTAL and OPUS trials, which showed that cetuximab was beneficial in patients with KRAS G13D mutations. As a result, she believes the role of the G13D is unclear and patients who test positive should be enrolled in clinical trials. The role of BRAF mutations in CRC has evolved, as more data becomes available. Axel Grothey, MD, explains that approximately 8% of patients with metastatic CRC have a BRAF mutation. Unfortunately, Grothey notes, BRAF mutations denote a poorer prognosis and a standard therapy currently does not exist. The treatment of BRAF mutant metastatic CRC is evolving, Lenz states. Moreover, he notes, these tumors seem to respond to immunotherapies. The need for effective treatment approaches in this space enhances the importance of molecular testing and enrollment in clinical trials. At this point, Bendell notes, research is just beginning to scratch the surface of what is possible in the treatment of CRC. The panel remains optimistic that a target will be found that shows dramatic responses, similar to those seen in lung cancer with ALK and EGFR and in breast cancer with HER2. View More From This Discussion Episode 1 Managing Adjuvant Treatment in Colorectal Cancer, Part I Dr.

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