Molecular studies and therapeutic targeting of Kaposi’s sarcoma herpesvirus (KSHV/HHV-8) oncogenesis

Kaposi’s sarcoma herpesvirus or human herpesvirus-8 (KSHV/HHV-8) is the etiological agent of Kaposi’s sarcoma (KS), an AIDS-defining angioproliferative neoplasm that continues to be a major global health problem and, of primary effusion lymphoma (PEL), a rare incurable B-cell lymphoma. This review describes the research from our laboratory and its collaborators to uncover molecular mechanisms of viral oncogenesis in order to develop new pathogenesis-based therapies to the KSHV-induced AIDS malignancies KS and PEL. They include the discovery of the viral angiogenic oncogene G protein-coupled receptor (vGPCR), the development of mouse models of KSHV and oxidative stress-induced KS, the identification of the role of Rac1-induced ROS in viral oncogenesis of KS and the development of novel therapeutic approaches able to target both latent and lytic oncogenic KSHV infection

Systematic review with meta-analysis: prevalence of prior and concurrent Barrett's oesophagus in oesophageal adenocarcinoma patients

BACKGROUND: The proportions of patients with oesophageal adenocarcinoma (OAC) diagnosed by Barrett’s oesophagus surveillance or with preexisting Barrett’s oesophagus are unclear. AIM: A systematic review and meta-analysis to estimate the prevalence of prior and concurrent Barrett’s oesophagus diagnosis among patients with OAC or oesophagogastric junction adenocarcinomas (OGJAC). METHODS: We searched PubMed and Embase to identify studies published 1966–1/8/2020 that examined the prevalence of prior (≥6 months) or concurrent Barrett’s diagnosis (at cancer diagnosis) among OAC and OGJAC patients. Random effects models estimated overall and stratified pooled prevalence rates. RESULTS: A total of 69 studies, including 33,002 OAC patients (53 studies) and 2,712 with OGJAC (28 studies) were included. The pooled prevalence of prior Barrett’s oesophagus diagnosis in OAC was 11.8% (95% confidence interval [CI] 8.4–15.6%). The prevalence of prior Barrett’s oesophagus diagnosis was higher in single-center resection studies (16.0%, 95%CI 8.7–24.9%) than population-based cancer registry studies (8.4%, 95%CI 5.5–11.9%). The prevalence of concurrent Barrett’s oesophagus in OAC was 56.6% (95%CI 48.5–64.6%). Studies with 100% early stage OAC had higher prevalence of concurrent Barrett’s oesophagus (91.3%, 95%CI 82.4–97.6%) than studies with <50% early OAC (39.7%, 95%CI 33.7–45.9%). In OGJAC, the prevalence of prior and concurrent Barrett’s oesophagus was 23.2% (95%CI 7.5–44.0%) and 26.3% (95%CI 17.8–35.7%), respectively. CONCLUSIONS: Most patients with OAC have Barrett’s oesophagus. Our meta-analysis found ~12% of OAC patients had prior Barrett’s diagnosis, but concurrent Barrett’s oesophagus was found in ~57% at the time of OAC diagnosis. This represents a considerable missed opportunity for Barrett’s oesophagus screening

Disrupting galectin-1 interactions with N-glycans suppresses hypoxia-driven angiogenesis in Kaposi's sarcoma

Kaposi’s sarcoma (KS), a multifocal vascular neoplasm linked to human herpesvirus-8 (HHV-8/KS-associated herpesvirus [KSHV]) infection, is the most common AIDS-associated malignancy. Clinical management of KS has proven to be challenging because of its prevalence in immunosuppressed patients and its unique vascular and inflammatory nature that is sustained by viral and host-derived paracrine-acting factors primarily released under hypoxic conditions. We show that interactions between the regulatory lectin galectin-1 (Gal-1) and specific target N-glycans link tumor hypoxia to neovascularization as part of the pathogenesis of KS. Expression of Gal-1 is found to be a hallmark of human KS but not other vascular pathologies and is directly induced by both KSHV and hypoxia. Interestingly, hypoxia induced Gal-1 through mechanisms that are independent of hypoxia-inducible factor (HIF) 1α and HIF-2α but involved reactive oxygen species–dependent activation of the transcription factor nuclear factor κB. Targeted disruption of Gal-1–N-glycan interactions eliminated hypoxia-driven angiogenesis and suppressed tumorigenesis in vivo. Therapeutic administration of a Gal-1–specific neutralizing mAb attenuated abnormal angiogenesis and promoted tumor regression in mice bearing established KS tumors. Given the active search for HIF-independent mechanisms that serve to couple tumor hypoxia to pathological angiogenesis, our findings provide novel opportunities not only for treating KS patients but also for understanding and managing a variety of solid tumors.Fil: Croci Russo, Diego Omar. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; ArgentinaFil: Salatino, Mariana. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; ArgentinaFil: Rubinstein, Natalia. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; ArgentinaFil: Cerliani, Juan Pablo. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); ArgentinaFil: Cavallin, Lucas E.. Miami University; Estados UnidosFil: Leung, Howard J.. Miami University; Estados UnidosFil: Ouyang, Jing. Dana Farber Cancer Institute; Estados UnidosFil: Ilarregui, Juan Martin. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); ArgentinaFil: Toscano, Marta Alicia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; ArgentinaFil: Domaica, Carolina Ines. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; ArgentinaFil: Croci, María C.. Universidad Nacional del Comahue; ArgentinaFil: Shipp, Margaret A.. Dana Farber Cancer Institute; Estados UnidosFil: Mesri, Enrique A.. Miami University; Estados UnidosFil: Albini, Adriana. Istituto di Ricovero e Cura a Carattere Scientifico MultiMedica; ItaliaFil: Rabinovich, Gabriel Adrian. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; Argentin