MDR1A deficiency restrains tumor growth in murine colitis-associated carcinogenesis

Abstract

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.

Overcoming multidrug resistance by knockout of ABCB1 gene using CRISPR/Cas9 system in SW620/Ad300 colorectal cancer cells

“…Although an inversed correlation between ABCB1 expression and cancer cell growth rate has been commonly known, deficiency in ABCB1 protein expression was shown to result in further restrained tumor growth in colitis‐associated colorectal cancer mouse model, which may be related to change in pathways involved in inflammatory response. 36 In this study, the growth curves obtained from MCTSs also revealed a slightly slower growth rate and less invasive expansion in MDR colon tumor spheroids led by ABCB1 silencing. However, the difference in growth rate was not significant when comparing SW620/Ad300‐ABCB1ko with SW620/Ad300 spheroids, possibly due to less significant involvement of inflammatory mediators in biological activities of SW620/Ad300 cells as the SW620 cell line is not derived from colitis‐associated colorectal cancer tissue.…”

Transcriptomic Analysis Suggests the M1 Polarization and Launch of Diverse Programmed Cell Death Pathways in Japanese Encephalitis Virus-Infected Macrophages

“…Although CCL12 (MCP-5) shares the same receptor (CCR2) as CCL2, it may have different biological activity than CCL2 [15,16]. CCL12 is a potent monocyte/macrophage chemoattractant, which also attracts lymphocytes and lung fibrocytes [17,18]. In West Nile virus (WNV) infection, CCL12 is significantly upregulated in the brain, which occurs much earlier than the upregulation of IFN-γ and TNF-α and thus is an early trigger of inflammation in the brain [19].…”

Biomarkers and experimental models for cancer immunology investigation

“…For example, the coculture of tumor cells and endothelial cells using a chambered submerged model can be used to study the efficacies of BCG therapy on immune cell proliferation and cytokine secretion 263 . Besides, the chambered submerged model can be used as an in vitro simulation of B cell immunotherapy 303 . Through the utilization of organotypic slice cultures of breast cancer tissue and lymph node tissue, it has been observed that lymph node slices cocultured with tumor slices exhibit greater immunosuppression compared with those cocultured with healthy tissue 274 …”

“…270,302,304 A coculture system can be used to simulate remote interactions between tumor cells and immune cells. 263,274,303 For example, the coculture of tumor cells and endothelial cells using a chambered submerged model can be used to study the efficacies of BCG therapy on immune cell proliferation and cytokine secretion. 263 Besides, the chambered submerged model can be used as an in vitro simulation of B cell immunotherapy.…”

“… 263 Besides, the chambered submerged model can be used as an in vitro simulation of B cell immunotherapy. 303 Through the utilization of organotypic slice cultures of breast cancer tissue and lymph node tissue, it has been observed that lymph node slices cocultured with tumor slices exhibit greater immunosuppression compared with those cocultured with healthy tissue. 274 …”