Important note: Information in this article was accurate in 1995. The state of the art may have changed since the publication date.
Overview of AIDS malignancies (Meeting abstract).
Proc Annu Meet Am Assoc Cancer Res; 35:658 1994. Unique Identifier : AIDSLINE ICDB/95606240 Broder S; NCI, Bethesda, MD 20892
Abstract:
Immunostimulation and immune dysregulation are major components of the pathogenesis of AIDS-related Kaposi's sarcoma (KS). The HIV Tat protein augments both viral and host gene expression. Basic fibroblast growth factor (b-FGF), an inflammatory cytokine produced by AIDS-KS cells as well as stromal cells, promotes angiogenesis and wound healing and interacts with Tat to induce proliferation of normal vascular cells. Tat induces AIDS-KS cells to produce a cascade of other inflammatory cytokines, creating an autocrine loop that drives AIDS-KS proliferation and angiogenesis. In addition, Tat binds to cell surface integrin receptors which, in turn, might lead to activation of genes whose products are involved in the enzymatic degradation of basement membranes. Such enzymes are the targets of TIMP-2, a protein that blocks tumor invasion by complexing with collagenases and also has direct anti-angiogenesis activity. TIMP-2 could have an important role in the therapy of AIDS-KS by inhibiting tumor invasion and angiogenesis. b-FGF is a logical molecular target for intervention. Antisense constructs to b-FGF and other cytokines offer the potential to inhibit the growth of KS-derived cells and block angiogenesis. Various components of signal transduction pathways activated by FGFs are targets for tyrosine kinase inhibitors or immunologic manipulations such as monoclonal antibodies or immunotoxins. Novel antisignaling agents (eg, the calcium channel blocker CAI, inhibitors of isoprenylation pathways, and the genistein) may also have potential clinical efficacy in KS. The EBV genome is present in roughly 2/3 of all AIDS lymphomas as a monoclonal episome, consistent with the notion that EBV infection precedes the malignant transformation. EBV genomic expression in these lymphomas is distinctive, with co-expression of both the latent EBV nuclear antigen (EBNA)-1 and latent membrane protein (LMP), an EBV antigen with transforming capabilities often expressed in other EBV-associated malignancies. With regard to the host genome, rearrangement of the c-myc gene is present in 40% of the HIV-associated, EBV-positive lymphomas (compared with 14% of non-HIV lymphomas). Additional host genomic features include mutations of the p53 tumor suppressor gene in about 70% of AIDS-related Burkitt's lymphomas (40% in non-AIDS Burkitt's), often linked to c-myc rearrangement and activation; loss of one or more segments of the long arm of chromosome 6 (6q21-23 and 6q25-27) in about 20% of all lymphomas including those associated with AIDS; and ras mutations in about 10-15% of AIDS-related Burkitt's lymphomas (in contrast to the absence of ras mutations in the non-HIV setting). Developmental therapeutic approaches include the use of a variety of monoclonal antibody conjugates, cytotoxic chemotherapy in conjunction with a variety of antiretrovirals (AZT, ddI) and hematopoietic stimulators (eg, IL-3 and CSFs) and immunorestoration with biologic response modifiers or bone marrow transplantation. The immunomodulatory monokine IL-12 (natural killer cell stimulatory factor) has a reciprocal relationship with IL-10, promoting cell-mediated immunity by driving the differentiation of naive CD4+ T cells into TH(1) cells. In this regard, IL-12 could have a special role as an immunostimulant in HIV infection, where both natural killer and TH(1) cell functions are defective. The aberrant expression of c-myc and p53 in a significant proportion of AIDS lymphomas suggests that antisense constructs targeting these genes could have potential clinical efficacy. Finally, transfection of tumor cells with the costimulatory molecule B7 would create a 'vaccine' that could directly recruit and activate CD8+ cells while bypassing the requirement for CD4+ cell cooperation in the generation of cellular immunity. This approach could be uniquely suited to overcoming a critical absence of functional CD4+ T cells, and potentially afford an effective strategy for therapy and prevention of these complications.
Keywords: Acquired Immunodeficiency Syndrome/*COMPLICATIONS/METABOLISM/ PATHOLOGY Antiviral Agents/THERAPEUTIC USE Cytokines/METABOLISM CD4-Positive T-Lymphocytes/IMMUNOLOGY Fibroblast Growth Factor/METABOLISM Gene Products, tat/METABOLISM Herpesvirus 4, Human/GENETICS Human Immunization Immunotherapy Interleukin-12/PHARMACOLOGY Lymphoma, AIDS-Related/GENETICS/THERAPY Protein p53/GENETICS Sarcoma, Kaposi's/ETIOLOGY/METABOLISM/PATHOLOGY ABSTRACT 950430
M9541148
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Important note: Information in this article was accurate in 1995. The state of the art may have changed since the publication date.
