Date Published: July 7, 2017
Publisher: Public Library of Science
Author(s): Eva Maria Hennenberg, Annette Eyking, Henning Reis, Elke Cario, Jörn Karhausen.
Patients with Ulcerative Colitis (UC) have an increased risk to develop colitis-associated colorectal cancer (CAC). Here, we found that protein expression of ABCB1 (ATP Binding Cassette Subfamily B Member 1) / MDR1 (multidrug resistance 1) was diminished in the intestinal mucosa of patients with active UC with or without CAC, but not in non-UC patients with sporadic colon cancer. We investigated the consequences of ABCB1/MDR1 loss-of-function in a common murine model for CAC (AOM/DSS). Mice deficient in MDR1A (MDR1A KO) showed enhanced intratumoral inflammation and cellular damage, which were associated with reduced colonic tumor size and decreased degree of dysplasia, when compared to wild-type (WT). Increased cell injury correlated with reduced capacity for growth of MDR1A KO tumor spheroids cultured ex-vivo. Gene expression analysis by microarray demonstrated that MDR1A deficiency shaped the inflammatory response towards an anti-tumorigenic microenvironment by downregulating genes known to be important mediators of cancer progression (PTGS2 (COX2), EREG, IL-11). MDR1A KO tumors showed increased gene expression of TNFSF10 (TRAIL), a known inducer of cancer cell death, and CCL12, a strong trigger of B cell chemotaxis. Abundant B220+ B lymphocyte infiltrates with interspersed CD138+ plasma cells were recruited to the MDR1A KO tumor microenvironment, concomitant with high levels of immunoglobulin light chain genes. In contrast, MDR1A deficiency in RAG2 KO mice that lack both B and T cells aggravated colonic tumor progression. MDR1A KO CD19+ B cells, but not WT CD19+ B cells, suppressed growth of colonic tumor-derived spheroids from AOM/DSS-WT mice in an ex-vivo co-culture system, implying that B-cell regulated immune responses contributed to delayed tumor development in MDR1A deficiency. In conclusion, we provide first evidence that loss of ABCB1/MDR1 function may represent an essential tumor-suppressive host defense mechanism in CAC.
Patients with long-term Ulcerative Colitis (UC) have an increased risk of developing colitis-associated colorectal cancer (CAC) . Initial extent  and duration  of chronic inflammation are recognized to be among the key risk factors. DNA damage and methylation caused by oxidative stress in chronic inflammation drive tumor development and progression . Microbiome-induced alterations in innate immune signaling may contribute to the development of intestinal inflammation and associated colon cancer in the susceptible individual . CAC appears to be distinct from sporadic colorectal cancer (CRC), both in pathophysiological and clinical features. It usually affects individuals at a younger age than the general population and demonstrates a more proximal and multifocal distribution in the colon. CAC progresses to invasive adenocarcinoma from flat and nonpolypoid dysplasia more frequently and rapidly than CRC . Some differences in the spectrum of genomic alterations were recently found in CAC compared with CRC . Allelic deletion of the p53 tumor suppressor gene occurs early in the process of tumorigenesis  and more frequent in CAC, while mutations in APC are relatively rare . But the mechanisms which may modulate tumor progression in CAC remain to be elucidated.
Reduced ABCB1/MDR1 mRNA expression has been associated with active UC  and early CRC . Loss of MDR1A gene function drives chronic colitis in mice [16, 17, 47]. The present study implies a previously unappreciated role of ABCB1/MDR1 in colonic tumor advancement under chronic inflammatory conditions. We found that lack of ABCB1/MDR1-mediated signals promoted a B cell-dominated tumor immunogenic microenvironment and resulted in an increase in tumor cell damage, which correlated with inhibition of inflammation-associated tumor growth.