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

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[superscript +/−] 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[superscript +]Gr-1[superscript +] myeloid cells (IMCs) with thioglycolate-induced peritonitis, DSS-induced colitis, and H. felis–induced gastritis. IL-8 was increased in colorectal 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[superscript +/−] mice compared with APCmin[superscript +/−] 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

Mice that express human interleukin-8 have increased mobilization of immature myeloid cells, which exacerbates inflammation and accelerates colon carcinogenesis

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 colorectal 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 APCmin+/- 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. © 2013 AGA Institute

Evidence for Treatment and Survival Disparities by Age in Pancreatic Adenocarcinoma A Population-Based Analysis

Objectives: Studies demonstrate safety and survival benefits of surgical resection in older individuals with pancreatic adenocarcinoma. We investigated treatment disparities by age. Methods: The Surveillance, Epidemiology, and End Results database for survival and treatment of pancreatic adenocarcinoma between 1983 and 2007 stratified by age: younger than 50 years, between 50 and 70 years, or older than 70 years. Kaplan-Meier curves and Cox proportional hazards models were used for survival differences, and logistic regression models were used for treatment disparities and the decision to refuse surgery. Results: A total of 45,509 patients had microscopically confirmed pancreatic adenocarcinoma. Of these, 7374 (16%) received surgery and 9842 (22%) received radiation. Younger patients were more likely to receive both surgery and radiation. The prevalence of surgery decreased from 21% for those younger than 50 years to 19% for those between 50 and 70 years to 13% for those older than 70 years (P 70 years) controlling for stage, sex, race, radiation, and surgery (P < 0.001). Increasing age negatively predicted the odds of receiving both surgery and radiation and increased the likelihood of refusing surgery. Conclusions: Treatment disparities exist by age despite advances in radiation and surgical treatment. Increased treatment in the elderly will increase overall survival from pancreatic adenocarcinoma