Lamellipodin-Deficient Mice: A Model of Rectal Carcinoma

• Published in: PloS one 2016-04, Vol.11 (4), p.e0152940-e0152940
• Main Authors: Miller, Cassandra L, Muthupalani, Sureshkumar, Shen, Zeli, Drees, Frauke, Ge, Zhongming, Feng, Yan, Chen, Xiaowei, Gong, Guanyu, Nagar, Karan K, Wang, Timothy C, Gertler, Frank B, Fox, James G
• Format: Article
• Language: English
• Subjects: Animals; Bioengineering; Biology and Life Sciences; Biomarkers; Carrier Proteins - genetics; CD11b antigen; Cell adhesion & migration; Colon; Colorectal cancer; Complications and side effects; Cytokines; Deoxyribonucleic acid; Disease Models, Animal; DNA; DNA Damage; Embryo transfer; Endemic species; Epithelial cells; Gastric cancer; Genetic aspects; Genetic transformation; Genotype & phenotype; Helicobacter infections; Helicobacter pylori; Hormone replacement therapy; Humans; In Situ Hybridization, Fluorescence; Infections; Inflammation; Inflammatory bowel disease; Intestine; Invasiveness; Laboratory animals; Lesions; Liver diseases; Medical research; Medicine; Medicine and Health Sciences; Membrane Proteins - genetics; Mice; Mice, Inbred C57BL; Mice, Knockout; Proteins; Rectal Neoplasms - genetics; Rectal Neoplasms - pathology; Rectal prolapse; Rectum; Research and Analysis Methods; Research facilities; Risk factors; Rodents; Stomach cancer; Studies; Transformation; Transgenic mice
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0152940

During a survey of clinical rectal prolapse (RP) cases in the mouse population at MIT animal research facilities, a high incidence of RP in the lamellipodin knock-out strain, C57BL/6-Raph1tm1Fbg (Lpd-/-) was documented. Upon further investigation, the Lpd-/- colony was found to be infected with multiple endemic enterohepatic Helicobacter species (EHS). Lpd-/- mice, a transgenic mouse strain produced at MIT, have not previously shown a distinct immune phenotype and are not highly susceptible to other opportunistic infections. Predominantly male Lpd-/- mice with RP exhibited lesions consistent with invasive rectal carcinoma concomitant to clinically evident RP. Multiple inflammatory cytokines, CD11b+Gr1+ myeloid-derived suppressor cell (MDSC) populations, and epithelial cells positive for a DNA damage biomarker, H2AX, were elevated in affected tissue, supporting their role in the neoplastic process. An evaluation of Lpd-/- mice with RP compared to EHS-infected, but clinically normal (CN) Lpd-/- animals indicated that all of these mice exhibit some degree of lower bowel inflammation; however, mice with prolapses had significantly higher degree of focal lesions at the colo-rectal junction. When Helicobacter spp. infections were eliminated in Lpd-/- mice by embryo transfer rederivation, the disease phenotype was abrogated, implicating EHS as a contributing factor in the development of rectal carcinoma. Here we describe lesions in Lpd-/- male mice consistent with a focal inflammation-induced neoplastic transformation and propose this strain as a mouse model of rectal carcinoma.