Adhesion Molecule Shows Promise for Treating Colitis

Philadelphia, PA, April 29, 2014 /3BL Media/ – The adhesion molecule CD146 plays a vital role in inflammation and offers a promising therapeutic target for treating inflammatory bowel disease (IBD) as well as preventing colitis-associated colorectal cancer, say scientists. Targeting CD146 with anti-CD146 antibody AA98, especially in combination with an anti-TNF-a antibody, showed promising results in mice. Their report is published in The American Journal of Pathology.

Enhanced CD146 expression has been reported on endothelial cells in intestinal biopsies from patients with inflammatory bowel disease. There have also been clinical observations that CD146 expression is associated with other inflammatory diseases such as rheumatoid arthritis, chronic renal failure, and diabetes. However, the mechanisms were unclear until now.

In the present study, the investigators set out to examine how CD146 functions in inflammatory diseases and, more importantly, to understand its role in chronic-inflammation-associated carcinogenesis. They found that overexpressed endothelial CD146 promoted the inflammatory responses in IBD, which further potentiated the occurrence of colitis-associated carcinogenesis (CAC). “Eliminating endothelial CD146 by conditional knockout in two different mouse models of colitis significantly reduced the severity of inflammation and decreased tumor incidence and tumor progression in a mouse model of CAC,” reports lead investigator Xiyun Yan, PhD, from the Key Laboratory of Protein and Peptide Pharmaceuticals, Institute of Biophysics, Chinese Academy of Sciences, Beijing.

To mimic the long-lasting and relapsing property of IBD, the team also established a chronic colitis mouse model and administrated an anti-CD146 antibody, AA98, after the onset of disease. Because IBD is a clinically heterogeneous disease with complex mechanisms, a combination of drugs targeting distinct biomarkers might be considered as a potential approach. Thus, they also tested the combined treatment of anti-CD146 antibody AA98 and anti-TNF-a antibody V1q in this model. Disease activity index and histological score were dramatically reduced in the AA98 treatment group and the V1q treatment group, especially the combination treatment group, compared with the mIgG treatment group.

“Current IBD treatment mainly focuses on inhibition of cytokines. Infliximab, an antibody against TNF-a, has been approved by the US Food and Drug Administration for treating ulcerative colitis (UC), and many inhibitors and antibodies against TNF-a are now under clinical evaluation. However, side effects such as increased risk of infection and even lymphoma have been indicated. Moreover, clinical trial data suggest that a considerable proportion of patients receiving anti-TNF-a therapy may become resistant to treatment in the first few years. Anti-adhesion molecule therapy could therefore be an alternative therapeutic intervention,” explains Dr. Yan.

The investigators also found that there was a decrease in blood vessels and lymphocytic cell infiltration, both in AA98-treated and V1q-treated mice, whereas a more significant decrease was observed in the combination treatment group. The expression levels of proinflammatory cytokines were also reduced.

“Our study provides the first evidence that endothelial CD146 plays a dual role on endothelium, facilitating leukocyte extravasations and angiogenesis, thus promoting inflammation,” says Dr. Yan. “Its involvement in the recruitment of inflammatory lymphocytes and promotion of angiogenesis may serve as a critical link between colitis and CAC. Although far more work needs to be done before bringing it to the clinic, targeting CD146 with AA98, especially in combination with an anti-TNF-a antibody, may be a therapeutic option in treating colitis, as well as a preventative method for CAC.”

There is growing evidence that chronic inflammation contributes to carcinogenesis, including gastrointestinal, lung, and prostate cancers. Patients suffering from UC, a major form of IBD, for more than 10 years are six to ten times more likely to develop colorectal cancer than the general population. UC is characterized by a long-lasting cycle of remission and exacerbations of ulceration of bowels, abdominal pain, diarrhea, bloody stool, and other systemic symptoms.

---

Notes for editors
“Targeting endothelial CD146 attenuates colitis and prevents colitis-associated carcinogenesis,” by Shu Xing, Yongting Luo, Zhihua Liu, Pengcheng Bu, Hongxia Duan, Dan Liu, Ping Wang, Jing Yang, Lina Song, Jing Feng, Dongling Yang, Zhihai Qin, and Xiyun Yan (DOI:http://dx.doi.org/10.1016/j.ajpath.2014.01.031), published in The American Journal of Pathology, Volume 184, Issue 5 (May 2014) published by Elsevier.

Full text of the article is available to credentialed journalists upon request; contact Eileen Leahy at +1 732 238 3628 or ajpmedia@elsevier.com. Journalists wishing to interview Professor Xiyun Yan may contact her directly at yanxy@ibp.ac.

This work was supported in part by grants from the National Natural Science Foundation of China, the National Basic Research Program of China (973 program).

About The American Journal of Pathology
The American Journal of Pathology, official journal of the American Society for Investigative Pathology, seeks to publish high-quality, original papers on the cellular and molecular biology of disease. The editors accept manuscripts that advance basic and translational knowledge of the pathogenesis, classification, diagnosis, and mechanisms of disease, without preference for a specific analytic method. High priority is given to studies on human disease and relevant experimental models using cellular, molecular, animal, biological, chemical, and immunological approaches in conjunction with morphology.

The leading global forum for reporting quality original research on cellular and molecular mechanisms of disease, The American Journal of Pathology is the most highly cited journal in Pathology – over 38,000 cites in 2012 – with an Impact Factor of 4.522 and Eigenfactor of 0.07599 according to the 2012 Journal Citation Reports^®, Thomson Reuters, and an h-index of 181 according to the 2011 SCImago Journal and Country Rank.

About Elsevier
Elsevier is a world-leading provider of information solutions that enhance the performance of science, health, and technology professionals, empowering them to make better decisions, deliver better care, and sometimes make groundbreaking discoveries that advance the boundaries of knowledge and human progress. Elsevier provides web-based, digital solutions — among them ScienceDirect, Scopus, Elsevier Research Intelligence and ClinicalKey — and publishes nearly 2,200 journals, including The Lancet and Cell, and over 25,000 book titles, including a number of iconic reference works.

The company is part of Reed Elsevier Group PLC, a world-leading provider of professional information solutions in the Science, Medical, Legal and Risk and Business sectors, which is jointly owned by Reed Elsevier PLC and Reed Elsevier NV. The ticker symbols are REN (Euronext Amsterdam), REL (London Stock Exchange), RUK and ENL (New York Stock Exchange).

Media contacts
Eileen Leahy
Elsevier
+1 732 238 3628
ajpmedia@elsevier.com

Dr. Chhavi Chauhan
Scientific Editor
The American Journal of Pathology
+1 301 634 7953
cchauhan@asip.org