Lamellipodin-Deficient Mice: A Model of Rectal Carcinoma.

Cassandra L Miller,Xiaowei Chen,Zeli Shen,Yan Feng,Frauke Drees,James G Fox,Karan K Nagar,Timothy C Wang,Sureshkumar Muthupalani,Guanyu Gong,Frank B Gertler,Zhongming Ge,Sergei Grivennikov

doi:10.1371/journal.pone.0152940

Cassandra L Miller, Xiaowei Chen + Show 11 more

Open Access

https://doi.org/10.1371/journal.pone.0152940

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Abstract

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.

Highlights

Rectal prolapse (RP) is a common clinical condition in laboratory mice and is often associated with lower bowel inflammation
We identified a transgenic mouse strain, the lamellipodin knockout (Lpd-/-), which had the highest incidence of RP of any single strain among the mice housed at MIT, comprising 26% of the mice with RP [8]
We report on a total of 19 cases of RP in Lpd-/- mice infected with enterohepatic Helicobacter species (EHS)

Summary

Introduction

Rectal prolapse (RP) is a common clinical condition in laboratory mice and is often associated with lower bowel inflammation. More proximal inflammation in the colon can result in thickened edematous tissue and tenesmus. These factors, coupled with the relatively short distal colon that is not rigidly fixed by serosa, provide pathophysiological basis for RP to occur with. Rectal Carcinoma in Lpd-/- Mice lower bowel inflammation [1,2,3]. In a recent survey of laboratory mice at our institution, we investigated cases of RP and identified patterns in mouse strain susceptibility, RP association with EHS, and determined the presence of unique histopathological findings [8]. We identified a transgenic mouse strain, the lamellipodin knockout (Lpd-/-), which had the highest incidence of RP of any single strain among the mice housed at MIT, comprising 26% of the mice with RP [8]

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