Mice That Express Human Interleukin-8 Have Increased Mobilization of Immature Myeloid Cells, Which Exacerbates Inflammation and Accelerates Colon Carcinogenesis

Abstract

BACKGROUND & AIMS Interleukin (IL)-8 has an important role in initiating inflammation in humans, attracting immune cells such as neutrophils through their receptors CXCR1 and CXCR2. IL-8 has been proposed to contribute to chronic inflammation and cancer. However, mice do not have the IL-8 gene, so human cancer cell lines and xenograft studies have been used to study the role of IL-8 in colon and gastric carcinogenesis. We generated mice that carry a bacterial artificial chromosome that encompasses the entire human IL-8 gene, including its regulatory elements (IL-8Tg mice). METHODS We studied the effects of IL-8 expression in APCmin+/− mice and IL-8Tg mice given azoxymethane and dextran sodium sulfate (DSS). We also examined the effects of IL-8 expression in gastric cancer in INS-GAS mice that overexpress gastrin and IL-8Tg mice infected with Helicobacter felis. RESULTS In IL-8Tg mice, expression of human IL-8 was controlled by its own regulatory elements, with virtually no messenger RNA or protein detectable under basal conditions. IL-8 was strongly up-regulated on systemic or local inflammatory stimulation, increasing mobilization of immature CD11b+Gr-1+ myeloid cells (IMCs) with thioglycolate-induced peritonitis, DSS-induced colitis, and H. felis–induced gastritis. IL-8 was increased in colo-rectal tumors from patients and IL-8Tg mice compared with nontumor tissues. IL-8Tg mice developed more tumors than wild-type mice following administration of azoxymethane and DSS. Expression of IL-8 increased tumorigenesis in APCmin+/− mice compared with APC-min+/− mice that lack IL-8; this was associated with increased numbers of IMCs and angiogenesis in the tumors. CONCLUSIONS IL-8 contributes to gastrointestinal carcinogenesis by mobilizing IMCs and might be a therapeutic target for gastrointestinal cancers.

MACC1 Induces Tumor Progression in Transgenic Mice and Colorectal Cancer Patients via Increased Pluripotency Markers Nanog and Oct4

“…It has been previously described that Apc Min mice develop splenomegaly (39). Some studies reported a correlation between the severity of the tumorigenesis and the spleen size (39,40). Consistently, we observed a very strong positive correlation between the spleen size and the number of tumors in the vil-MACC1/Apc Min and Apc Min mice (Supplementary Fig.…”

Neutralization of IL-8 decreases tumor PMN-MDSCs and reduces mesenchymalization of claudin-low triple-negative breast cancer

“…The chemotactic role of IL-8 toward immune cell populations includes the ability of this chemokine to recruit MDSCs to the tumor microenvironment (27,28). Although there is no homolog of IL-8 in the mouse genome, the IL-8 receptor CXCR2 is expressed in murine MDSCs, and we hypothesize that human IL-8 secreted by MDA-MB-231 cancer cells could bind murine CXCR2 and elicit the recruitment of MDSCs into the tumor.…”

RelA regulates CXCL1/CXCR2-dependent oncogene-induced senescence in murine Kras-driven pancreatic carcinogenesis

“…To determine the relevance of the observed link between the activation of RelA and CXCL1-dependent OIS, we used transgenic mice expressing IL8, the human orthologue of murine CXCL1 [Tg(IL8), hereafter referred to as IL-8tg]. IL-8tg mice carry a bacterial artificial chromosome that encompasses the entire human IL8 gene, including its regulatory elements (23). This mouse line was crossed to the Kras RelA strain to obtain LSL-Kras Thus, these results strongly support the notion that CXCL1 contributes to the regulation of OIS via RelA activation in vivo and in vitro.…”