Research Article: MDR1A deficiency restrains tumor growth in murine colitis-associated carcinogenesis

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.

Partial Text

Patients with long-term Ulcerative Colitis (UC) have an increased risk of developing colitis-associated colorectal cancer (CAC) [1]. Initial extent [2] and duration [3] 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 [4]. Microbiome-induced alterations in innate immune signaling may contribute to the development of intestinal inflammation and associated colon cancer in the susceptible individual [5]. 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 [6]. Some differences in the spectrum of genomic alterations were recently found in CAC compared with CRC [7]. Allelic deletion of the p53 tumor suppressor gene occurs early in the process of tumorigenesis [8] and more frequent in CAC, while mutations in APC are relatively rare [7]. 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 [46] and early CRC [14]. 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.




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