The insulin receptor is essential for virus-induced tumorigenesis of Kaposi's sarcoma

Rose, Patrick P.; Carroll, Julie M.; Carroll, Patrick A.; DeFilippis, Victor R.; Lagunoff, Michael; Moses, Ashlee V.; Roberts, Charles T.; Früh, Klaus

doi:10.1038/sj.onc.1210006

Cited by 30 publications

(30 citation statements)

References 31 publications

(40 reference statements)

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“…IR overexpression either in 3T3 fibroblasts or in MCF10 human breast immortalized cells enhances cell proliferation in response to insulin and induces a ligand-dependent transformed phenotype (Giorgino et al 1991, Mastick et al 1994. In endothelial cells infected by Kaposi sarcoma-associated herpes virus, functional IR is essential for transformation (Rose et al 2007).…”

Section: Ir Expression and Function In Cancer Cellsmentioning

confidence: 99%

Insulin receptor and cancer

Belfiore

Malaguarnera²

2011

Endocrine-Related Cancer

241

223

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The widespread epidemic of obesity and type 2 diabetes has raised concern for the impact of these disorders as risk factors for cancer and has renewed the interest for studies regarding the involvement of hyperinsulinemia and insulin receptor (IR) in cancer progression. Overexpression of IR in cancer cells may explain their increased sensitivity to hyperinsulinemia. Moreover, IR isoform A (IR-A) together with autocrine production of its ligand IGF2 is emerging as an important mechanism of normal and cancer stem cell expansion and is a feature of several malignancies. De novo activation of the IR-A/IGF2 autocrine loop also represents a mechanism of resistance to anticancer therapies. Increasing knowledge of the IR role in cancer has important implications for cancer prevention, which should include control of insulin resistance and hyperinsulinemia in the population and meticulous evaluation of new antidiabetic drugs for their metabolic:mitogenic ratio. We are now aware that several anticancer treatments may induce or worsen insulin resistance that may limit therapy efficacy. Future anticancer therapies need to target the IR-A pathway in order to inhibit the tumor promoting effect of IR without impairing the metabolic effect of insulin.

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Section: Ir Expression and Function In Cancer Cellsmentioning

confidence: 99%

Insulin receptor and cancer

Belfiore

Malaguarnera²

2011

Endocrine-Related Cancer

241

223

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“…In our cell culture system, most but not all E-DMVEC are latently infected with KSHV. However, spindle cell-containing foci forming upon postconfluent growth are enriched for latently infected cells (43). Therefore, we wanted to explore whether treatment with a CTSB inhibitor changed the ratio of infected to uninfected E-DMVEC.…”

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confidence: 99%

“…Unexpectedly, secretion of CTSB was inhibited in latently infected endothelial cells. CTSB is retained by the insulin-like growth factor-II receptor/mannose-6-phosphate receptor (IGF-IIR/M6PR), which we previously reported to be transcriptionally induced during KSHV-mediated transformation of E-DMVEC (43). Therefore, in contrast to the increased secretion of CTSB observed in several other tumor models, CTSB is retained in the endosomal/lysosomal compartment in KS, where it likely regulates the processing of growth factors or growth factor binding proteins.…”

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confidence: 99%

“…Despite the restricted viral gene expression program, latent infections are associated with a dramatic reprogramming of the cellular transcriptome and proteome (4,38,39,55). Several virus-induced host cell proteins are required to support postconfluent growth, including c-Kit, hemoxygenase, RDC-1, Neuritin, and the insulin receptor (30,39,42,43).One of the hallmarks of KS is aberrant neoangiogenesis by proliferating spindle cells, resulting in abnormal vasculature. Neoangiogenesis involves the degradation of extracellular matrix by proteases, a process that frequently involves cysteine proteases of the cathepsin family (6,21,22,53).…”

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Insulin-Like Growth Factor II Receptor-Mediated Intracellular Retention of Cathepsin B Is Essential for Transformation of Endothelial Cells by Kaposi's Sarcoma-Associated Herpesvirus

Rose

Bogyo

Moses

et al. 2007

J Virol

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Kaposi's sarcoma-associated herpesvirus (KSHV) is the pathological agent of Kaposi's sarcoma (KS),Kaposi's sarcoma-associated herpesvirus/human herpesvirus 8 (KSHV/HHV8) belongs to the gammaherpesvirus subfamily and is the pathological agent of Kaposi's sarcoma (KS) and of lymphoproliferative disorders in B cells (20). KS is a mesenchymal tumor generally targeting the skin and soft tissue organs. The sarcoma is composed of interweaving bands of vascularizing spindle cells of endothelial origin, frequently associated with infiltrating inflammatory cells (8,35). AIDS has been most commonly associated with KS, although other forms of KS exist independently of human immunodeficiency virus infection, e.g., classic, endemic, and iatrogenic KS (15,35). Antiretroviral treatments against human immunodeficiency virus have effectively reduced the prevalence of AIDS-associated KS; however, the incidence of iatrogenic KS has increased 400% relative to the population growth in North America. This is most likely due to an increase in the number of organ transplant recipients (46).The development of several in vitro systems that rely on infection of primary or immortalized endothelial cells by KSHV has greatly advanced our understanding of virus-host cell interaction during tumorigenesis (31). Dermal microvascular endothelial cells stably transfected with the oncogenes E6 and E7 of human papillomavirus (E-DMVEC) are immortalized but remain contact inhibited, grow as discrete monolayers with a cobblestone phenotype, and enter senescence if not passaged after attaining confluence (37). Upon infection with KSHV, E-DMVEC develop a spindle cell phenotype, lose contact inhibition, form foci when cultured postconfluence, and acquire the ability to form colonies in soft agar (37). As in KS tumors, viral gene expression in E-DMVEC is largely restricted to open reading frame 71 (ORF71 [vFLIP]), ORF72 (vCyclin), ORF73 (latency-associated nuclear antigen [LANA]), and kaposin, and only a few cells spontaneously enter the lytic cycle of viral replication. Despite the restricted viral gene expression program, latent infections are associated with a dramatic reprogramming of the cellular transcriptome and proteome (4,38,39,55). Several virus-induced host cell proteins are required to support postconfluent growth, including c-Kit, hemoxygenase, RDC-1, Neuritin, and the insulin receptor (30,39,42,43).One of the hallmarks of KS is aberrant neoangiogenesis by proliferating spindle cells, resulting in abnormal vasculature. Neoangiogenesis involves the degradation of extracellular matrix by proteases, a process that frequently involves cysteine proteases of the cathepsin family (6,21,22,53). Despite this important role of cathepsins in many cancers, the role of cathepsin function in KS development has not been studied so far. Cathepsins are part of the papain subfamily within the cysteine protease superfamily. Most cathepsins are ubiquitously expressed in lysosomes and play a role in protein degradation and processing. In addition to these housekeep...

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High prevalence of HHV8 infection and specific killer cell immunoglobulin-like receptors allotypes in Sardinian patients with type 2 diabetes mellitus

et al. 2013

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The development of type 2 diabetes is thought to involve both environmental, possibly infectious, and genetic factors. Recently, a high prevalence of human herpesvirus 8 (HHV8) infection was observed in type 2 diabetes patients, and specific killer cell immunoglobulin-like receptors (KIR) allotypes were associated to both increased susceptibility to herpesvirus infection and risk to develop diabetes. However, no clear gene-disease or virus-disease associations have been established. To investigate the possible interplay between HHV8 infection, KIR allotype and type 2 diabetes, virus prevalence and KIR genotype were analyzed by PCR in 168 patients affected by type 2 diabetes and 108 control individuals belonging to the Sardinian population. Results showed a significant increase of HHV8 prevalence in type 2 diabetes patients versus controls (57% vs. 17%, P < 0.001), and a significant increase of KIR2DL2/DS2 homozygosity in diabetes patients infected with HHV8 compared to uninfected ones (64% vs. 14%, P < 0.0001), resulting in a significant OR of 11.31. In addition, the analysis of the frequency of the KIR2DL2/DS2 receptor and its HLA-C1 ligand, accordingly to the status of HHV8 infection, showed a significant increased correlation between KIR2DL2/DS2, type 2 diabetes and HLA-C1C1 genotype in the type 2 diabetes patients infected with HHV8 compared to uninfected ones (62% vs. 15%, P < 0.0001, OR = 8.64). These findings provide preliminary evidence that HHV8 infection might be a cofactor for type 2 diabetes in a specific subset of genetically susceptible individuals, and suggest the possibility that such patients might have an impaired immune-mediated component contributing to the development of type 2 diabetes.

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The insulin receptor is essential for virus-induced tumorigenesis of Kaposi's sarcoma

Cited by 30 publications

References 31 publications

Insulin receptor and cancer

Insulin receptor and cancer

Insulin-Like Growth Factor II Receptor-Mediated Intracellular Retention of Cathepsin B Is Essential for Transformation of Endothelial Cells by Kaposi's Sarcoma-Associated Herpesvirus

High prevalence of HHV8 infection and specific killer cell immunoglobulin-like receptors allotypes in Sardinian patients with type 2 diabetes mellitus

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