The cytomegalovirus-encoded chemokine receptor US28 promotes intestinal neoplasia in transgenic mice

Abstract

US28 is a constitutively active chemokine receptor encoded by CMV (also referred to as human herpesvirus 5), a highly prevalent human virus that infects a broad spectrum of cells, including intestinal epithelial cells (IECs). To study the role of US28 in vivo, we created transgenic mice (VS28 mice) in which US28 expression was targeted to IECs. Expression of US28 was detected in all IECs of the small and large intestine, including in cells expressing leucine rich repeat containing GPCR5 (Lgr5), a marker gene of intestinal epithelial stem cells. US28 expression in IECs inhibited glycogen synthase 3β (GSK-3β) function, promoted accumulation of β-catenin protein, and increased expression of Wnt target genes involved in the control of the cell proliferation. VS28 mice showed a hyperplastic intestinal epithelium and, strikingly, developed adenomas and adenocarcinomas by 40 weeks of age. When exposed to an inflammation-driven tumor model (azoxymethane/dextran sodium sulfate), VS28 mice developed a significantly higher tumor burden than control littermates. Transgenic coexpression of the US28 ligand CCL2 (an inflammatory chemokine) increased IEC proliferation as well as tumor burden, suggesting that the oncogenic activity of US28 can be modulated by inflammatory factors. Together, these results indicate that expression of US28 promotes development of intestinal dysplasia and cancer in transgenic mice and suggest that CMV infection may facilitate development of intestinal neoplasia in humans.

Chemokines in cancer related inflammation

“…vGPCR acts as a transforming receptor in vitro and causes vascular lesions in transgenic mice, thus behaving as an oncogene [16]. Another example is the chemokine receptor US28 encoded by Cytomegalovirus; transgenic mice in which US28 expression was targeted to intestinal epithelial cells developed intestinal adenoma and carcinoma [17].…”

Discordant humoral and cellular immune responses toCytomegalovirus(CMV) in glioblastoma patients whose tumors are positive for CMV

“…7 These findings imply that HCMV affects tumor progression, consistent with substantial evidence that HCMV has an oncomodulatory or even a direct oncogenic role in tumor development. [10][11][12][13][14] To determine whether treatment for HCMV improves the prognosis for GBM patients, we performed an exploratory clinical study, Valcyte Treatment of Glioblastoma Patients in Sweden (VIGAS), to assess the safety and potential efficacy of valganciclovir as an add-on therapy. 15 Forty-two patients with GBM were enrolled and received valganciclovir or placebo for 24 weeks in combination with temozolomide and/or radiation therapy.…”

Promotion of Tumorigenesis and Clinical Implications of Viral Infection in Breast Cancer

“…US28, a G protein-coupled receptor encoded by HCMV, affects the Wnt signaling pathway by activating beta catenin and induces oncogenesis in vivo [106]. Activated beta catenin is frequently detected in invasive breast cancer and has a high impact on worsens patient outcome [107].…”

“…HCMV infection enhances the production of potential inflammatory factors, including prostaglandin E2 and leukotriene B4, by inducing expression of COX-2 and 5-lipoxygenase, respectively. These inflammatory factors are also involved in cellular proliferation and migration, angiogenesis, and metastasis formation and are targets for nonsteroidal antiinflammatory drugs (NSAIDs) [106,114,115]. Interestingly, NSAIDs also have anti-HCMV activity [116].…”

“…Of note, HCMV increases VEGF production. This effect is mediated by US28, an HCMV-encoded chemokine receptor homologue [120] that may be oncomodulatory or even oncogenic [106,114]. US28 protein expression enhances angiogenesis and cellular proliferation by increasing the release of IL-6 and VEGF and the phosphorylation of STAT-3 [106,114].…”