title: HIV infection accelerates gastrointestinal tumor outgrowth in NSG-HuPBL mice.
abstract: HIV infection is a risk factor for the tumorigenesis including non-AIDS-defining cancers such as those of the gastrointestinal tract. However, the mechanisms underlying such cancer outgrowth are still unknown. Furthermore, combined HIV/cancer studies are difficult to evaluate using primate models or in the clinical patient setting. To understand the mechanisms of tumor outgrowth in the context of HIV infection, we adopted a humanized mouse model permissive to infection and cancer as well as an in vivo humanized mouse challenge with colon cancer in the context of HIV infection. Immunodeficient NOD SCID IL-2R(-/-) mice were immunologically reconstituted by adoptive transfer of 10(7) HIV-negative donor peripheral blood leukocytes and challenged with 10(6) HCT116 human colon cancer cells. A group of mice was treated with antiretroviral therapy. Tumor microenvironment and epithelial tissues in the context of HIV infection were analyzed using immunohistochemistry. We demonstrate that HIV-infected humanized mice develop significantly larger tumors than uninfected mice (p<0.05). Epithelial cell proliferation in HIV-infected mice is significantly enhanced in comparison to proliferation in uninfected mice (p<0.01). Moreover, the activation of β-catenin, an important step in intestinal epithelial cell proliferation and tumorigenesis, is elevated in the tumors of HIV-infected mice (p<0.0001). Importantly, antiretroviral therapy reverses these pathological processes independently of CD4(+) T cell return. These findings model the ability of HIV infection to result in tumor outgrowth that is evident in HIV-positive patients and lend insight into previously unrecognized mechanisms that may underlie this pathology.
authors.affiliation: 1 Department of Biochemistry, Rush University Medical Center , Chicago, Illinois.
authors.forename: Rong
authors.initials: R
authors.lastname: Lu
authors.forename: Shaoping
authors.initials: S
authors.lastname: Wu
authors.forename: Yongguo
authors.initials: Y
authors.lastname: Zhang
authors.forename: Yinglin
authors.initials: Y
authors.lastname: Xia
authors.forename: Erica J
authors.initials: EJ
authors.lastname: Huelsmann
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Lacek
authors.forename: Arman
authors.initials: A
authors.lastname: Nabatiyan
authors.forename: Maureen H
authors.initials: MH
authors.lastname: Richards
authors.forename: Srinivas D
authors.initials: SD
authors.lastname: Narasipura
authors.forename: Victoria
authors.initials: V
authors.lastname: Lutgen
authors.forename: Honglei
authors.initials: H
authors.lastname: Chen
authors.forename: Howard L
authors.initials: HL
authors.lastname: Kaufman
authors.forename: Di
authors.initials: D
authors.lastname: Chen
authors.forename: Lena
authors.initials: L
authors.lastname: Al-Harthi
authors.forename: Andrew
authors.initials: A
authors.lastname: Zloza
authors.forename: Jun
authors.initials: J
authors.lastname: Sun
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D044966:Anti-Retroviral Agents / Q000627:therapeutic use; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D063646:Carcinogenesis; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004195:Disease Models, Animal; D005770:Gastrointestinal Neoplasms / Q000276:immunology* / Q000473:pathology* / Q000821:virology; D045325:HCT116 Cells; D015658:HIV Infections / Q000188:drug therapy / Q000276:immunology* / Q000821:virology; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D017708:Leukocyte Transfusion; D007962:Leukocytes / Q000276:immunology*; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D009374:Neoplasms, Experimental / Q000276:immunology / Q000473:pathology; D015375:Receptors, Interleukin-2 / Q000235:genetics; D051176:beta Catenin / Q000096:biosynthesis
chemical_list: D044966:Anti-Retroviral Agents; D015375:Receptors, Interleukin-2; D051176:beta Catenin