KSHV-Mediated Angiogenesis in Tumor Progression

Purushothaman, Pravinkumar; Uppal, Timsy; Sarkar, Roni; Verma, Subhash C.

doi:10.3390/v8070198

Cited by 39 publications

(61 citation statements)

References 288 publications

(315 reference statements)

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“…Inflammatory cytokine secretion from KSHV-infected cells plays an important role in the pathogenesis of KS and PEL (38). To explore the effects of the drug combination on cytokine secretion, Luminex assays were employed to measure the amount of cytokine secreted into tissue culture supernatants in response to drug treatments.…”

Section: Resultsmentioning

confidence: 99%

Oncolytic Reactivation of KSHV as a Therapeutic Approach for Primary Effusion Lymphoma

Zhou

Shimoda

Olney

et al. 2017

Molecular Cancer Therapeutics

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Primary effusion lymphoma (PEL) is an aggressive subtype of non-Hodgkin lymphoma caused by Kaposi’s sarcoma-associated herpesvirus (KSHV) infection. Currently treatment options for patients with PEL are limited. Oncolytic viruses have been engineered as anti-cancer agents and have recently shown increased therapeutic promise. Similarly, lytic activation of endogenous viruses from latently infected tumor cells can also be applied as a cancer therapy. In theory, such a therapeutic strategy would induce oncolysis by viral replication, while simultaneously stimulating an immune response to viral lytic cycle antigens. We examined the combination of the FDA-approved drug PEP005 (ingenol-3-angelate) with epigenetic drugs as a rational therapeutic approach for KSHV-mediated malignancies. JQ1, a bromodomain and extra terminal protein (BET) inhibitor, in combination with PEP005, not only robustly induced KSHV lytic replication, but also inhibited IL-6 production from PEL cells. Using the dosages of these agents that was found to be effective in reactivating HIV (as a means to clear latent virus with HAART therapy), we were able to inhibit PEL growth in vitro and delay tumor growth in a PEL xenograft tumor model. KSHV reactivation was mediated by activation of NF-κB pathway by PEP005, which led to increased occupancy of RNA polymerase II onto the KSHV genome. RNA-sequencing analysis further revealed cellular targets of PEP005, JQ1, and the synergistic effects of both. Thus, combination of PEP005 with a BET inhibitor may be considered as a rational therapeutic approach for the treatment of PEL.

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Section: Resultsmentioning

confidence: 99%

Oncolytic Reactivation of KSHV as a Therapeutic Approach for Primary Effusion Lymphoma

Zhou

Shimoda

Olney

et al. 2017

Molecular Cancer Therapeutics

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“…Current treatment options for KS include HAART and chemotherapy in the form of liposomal doxorubicin, liposomal daunorubicin, vincristine, bleomycin, etoposide and paclitaxel 14 15. The antiangiogenic drugs, imatinib, sorafenib, bevacizumab and sirolimus, have been used in some cases to counter disease progression and induce regression 16. In cases of single, remote lesions without metastasis, radiotherapy or surgery can prove to be effective forms of treatment 15…”

Section: Discussionmentioning

confidence: 99%

Non-cutaneous AIDS-associated Kaposi’s sarcoma presenting as recurrent rectal abscesses

Schulberg

Al-Feghali

Bain³

et al. 2018

BMJ Case Reports

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Kaposi's sarcoma is a fatal disease that typically presents with cutaneous manifestations in immunocompromised individuals. There are a small number of documented cases where patients diagnosed with this disease present without cutaneous lesions. We present a 35-year-old man with recurrent rectal abscesses and fistula-in-ano, which required multiple drainage procedures. Further investigation revealed a diagnosis of HIV-AIDS, and biopsy of a rectal mass confirmed the diagnosis of visceral Kaposi's sarcoma, despite the absence of cutaneous involvement. Workup revealed hepatic metastasis and a second pulmonary primary malignancy. The patient denied chemotherapy or further intervention and was subsequently lost to follow-up. Prompt diagnosis of Kaposi's sarcoma and initiation of treatment is vital to decrease disease progression. A high index of suspicion should be present in immunocompromised patients, and clinicians must recognise atypical presentations in order to improve long-term survival.

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“…HHV-8 is a DNA virus whose genome consists of a large 165 kb double-stranded DNA molecule and is enveloped by an icosahedral capsid. The virus was originally isolated from KS lesions from an AIDS patient and has been linked to other malignancies besides KS, including primary effusion lymphoma, body cavity-based lymphoma, multicentric Castleman’s disease, germinotropic lymphoproliferative disease, multiple myeloma, angiosarcomas, malignant skin tumors, and squamous cell carcinomas 73. In KS lesions, most of the cells infected by the virus are in the latent phase and do not proliferate or express angiogenic cytokines.…”

Section: Oncogenic Viruses Angiogenesis and Aids-related Cancersmentioning

confidence: 99%

“…In KS lesions, most of the cells infected by the virus are in the latent phase and do not proliferate or express angiogenic cytokines. A small percentage remain active and express angiogenic cytokines such as cytokines such as VEGF, IL-6, CXCL8, and bFGF 73. Multiple cell types can be infected by KHSV, but the infection of endothelial cells plays a major role in viral proliferation and angiogenesis.…”

Section: Oncogenic Viruses Angiogenesis and Aids-related Cancersmentioning

confidence: 99%

“…The pro-angiogenic activities of vIL-6 are enhanced through interaction with HIV-1-encoded Nef protein 76. vIL-6 is capable of initiating multiple downstream pathways transcription factors and REs, including JAK/STAT, MAPK, PI3K/AKT, STAT1/3, STAT5, IL-6 RE, C/EBP, and c-jun 73. The KSHV homolog of the angiogenic IL-8 receptor, viral G-protein-coupled receptor (vGPCR) controls the secretion of various angiogenic factors.…”

Section: Oncogenic Viruses Angiogenesis and Aids-related Cancersmentioning

confidence: 99%

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Abnormalities in alternative splicing of angiogenesis-related genes and their role in HIV-related cancers

Mthembu¹,

Mbita²,

Hull³

et al. 2017

HIV

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Alternative splicing of mRNA leads to an increase in proteome biodiversity by allowing the generation of multiple mRNAs, coding for multiple protein isoforms of various structural and functional properties from a single primary pre-mRNA transcript. The protein isoforms produced are tightly regulated in normal development but are mostly deregulated in various cancers. In HIV-infected individuals with AIDS, there is an increase in aberrant alternative splicing, resulting in an increase in HIV/AIDS-related cancers, such as Kaposi’s sarcoma, non-Hodgkin’s lymphoma, and cervical cancer. This aberrant splicing leads to abnormal production of protein and is caused by mutations in cis-acting elements or trans-acting factors in angiogenesis-related genes. Restoring the normal regulation of alternative splicing of angiogenic genes would alter the expression of protein isoforms and may confer normal cell physiology in patients with these cancers. This review highlights the abnormalities in alternative splicing of angiogenesis-related genes and their implication in HIV/AIDS-related cancers. This allows us to gain an insight into the pathogenesis of HIV/AIDS-related cancer and in turn elucidate the therapeutic potential of alternatively spliced genes in HIV/AIDS-related malignancies.

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KSHV-Mediated Angiogenesis in Tumor Progression

Cited by 39 publications

References 288 publications

Oncolytic Reactivation of KSHV as a Therapeutic Approach for Primary Effusion Lymphoma

Oncolytic Reactivation of KSHV as a Therapeutic Approach for Primary Effusion Lymphoma

Non-cutaneous AIDS-associated Kaposi’s sarcoma presenting as recurrent rectal abscesses

Abnormalities in alternative splicing of angiogenesis-related genes and their role in HIV-related cancers

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