Lymphatic Reprogramming by Kaposi Sarcoma Herpes Virus Promotes the Oncogenic Activity of the Virus-Encoded G-protein Coupled Receptor.

Aug 2012

Aguilar B, Choi I, Choi D, Chung HK, Lee S, Yoo J, Lee YS, Maeng YS, Lee HN, Park E, Kim KE, Kim NY, Baik JM, Jung JU, Koh CJ, Hong YK.

Source

Surgery and Biochemistry and Molecular Biology, University of Southern California.

Abstract

Kaposi sarcoma (KS), the most common cancer in HIV-positive individuals, is caused by endothelial transformation mediated by the KS herpes virus (KSHV)-encoded G-protein coupled receptor (vGPCR). Infection of blood vascular endothelial cells (BECs) by KSHV reactivates an otherwise silenced embryonic program of lymphatic differentiation. Thus, KS tumors express numerous lymphatic endothelial cell (LEC)-signature genes. A key unanswered question is how lymphatic reprogramming by the virus promotes tumorigenesis leading to KS formation. In this study, we present evidence that this process creates an environment needed to license the oncogenic activity of vGPCR. We found that the G-protein regulator RGS4 is an inhibitor of vGPCR that is expressed in BECs, but not in LECs. RGS4 was downregulated by the master regulator of LEC differentiation PROX1, which is upregulated by KSHV and directs KSHV-induced lymphatic reprogramming. Moreover, we found that KSHV upregulates the nuclear receptor LRH1, which physically interacts with PROX1 and synergizes with it to mediate repression of RGS4 expression. Mechanistic investigations revealed that RGS4 reduced vGPCR-enhanced cell proliferation, migration, VEGF expression and Akt activation and to suppress tumor formation induced by vGPCR. Our findings resolve long-standing questions about the pathological impact of KSHV-induced reprogramming of host cell identity, and they offer biological and mechanistic insights supporting the hypothesis that a lymphatic microenvironment is more favorable for KS tumorigenesis.

Cancer Research

or

PubMed

Lymphangioma-Like Kaposi Sarcoma.

August 2012

We report on a recent lesion in a 75-year-old woman who

had been diagnosed with classic Kaposi sarcoma (KS) 8 years earlier, at which time she presented with plaques on the right thigh and right forearm (Fig. 1A) and no metastasis was detected. Findings from the initial biopsy of the forearm lesions were compatible with nodular KS.

During the 8-year follow-up, the patient developed 7 recurrent skin tumors on the forearm and legs. Each tumor had the same clinical appearance in the form of plaques (Fig. 1B), and no systemic involvement was detected at any time. The lesions were treated with liposomal doxorubicin. Biopsies were taken from the forearm at each recurrence and histology continued to show findings consistent with nodular KS mixed with lymphangioma-like areas. 

These areas were comprised of irregularly-dilated ectatic vascular spaces in the reticular dermis that were lined by moderately atypical endothelial cells. These spaces were greater in number and size than normal lymphatic vessels (Fig. 2). Immunohistochemistry showed strong CD34 positivity. Endothelial cells lining the lymphangioma-like areas of the tumor were

also positive on staining with human herpes virus type 8

(HHV-8) antibody (Fig. 2C) and the lymphatic endothelial

marker podoplanin (D2-40) (Fig. 2D). Based on these findings, the patient was diagnosed with lymphangioma-like KS.

Seven months after completing the most recent cycle of

chemotherapy with doxorubicin, the patient presented with a serious recurrence consisting of localized, multinodular, ulcerated lesions on both legs but more severe on the right thigh; severe lymphedema was also noted (Fig. 1C). She was given radiotherapy, second-line chemotherapy with paclitaxel (taxol), and thorough local treatments. At the time of writing the lesions remained ulcerated and had not changed in size. The patient attended scheduled follow-up visits and did not show signs of systemic spread of disease.

Full Text Article with Diagnostic Images

Elsevier

Kaposi's sarcoma: case report and treatment options.

Oct 2011

Tan WC, Chan LC.

Source

Department of Dermatology, Hospital Pulau Pinang, Penang, Malaysia. tanwooichiang@yahoo.com

Abstract

Kaposi's sarcoma (KS) is strongly associated with Human Herpes Virus 8 (HHV8) and Human Immunodeficiency Virus infection (HIV). It was the first malignancy to be linked with Acquired Immunodeficiency Syndrome (AIDS). We report a case of Kaposi's sarcoma in a newly diagnosed retroviral homosexual patient with CD4 count of 21. He had multiple firm discrete violaceous plaques and nodules scattered over the face, scalp, hard palate, trunk and genitalia. Biopsy of a skin nodule over the trunk and a biopsy of a lesion from the gastric mucosa confirmed Kaposi's sarcoma. He was started on Highly Active Antiretroviral Therapy (HAART) and cryotherapy (liquid nitrogen) was given for the lesions over the skin. He responded well to treatment. Liquid nitrogen is a useful adjuvant treatment for Kaposi's sarcoma.

PubMed

Imiquimod 5% cream for treatment of HIV-negative Kaposi's sarcoma skin lesions: A phase I to II, open-label trial in 17 patients.

Imiquimod 5% cream for treatment of HIV-negative Kaposi's sarcoma skin lesions: A phase I to II, open-label trial in 17 patients.
J Am Acad Dermatol. 2008 Apr
Célestin Schartz NE, Chevret S, Paz C, Kerob D, Verola O, Morel P, Lebbé C.
Department of Dermatology 2, Hôpital Saint Louis AP-HP, Paris, France. noel.schartz@noos.fr

BACKGROUND: Kaposi's sarcoma (KS), a virus-associated neoplasm, can be treated locally or systemically with interferon alfa. Therefore, imiquimod, an immune response modifier able to induce interferon-alpha secretion in situ, could prove a good local treatment for KS skin lesions.

OBJECTIVE: We sought to determine the efficacy and safety of imiquimod 5% cream for the topical treatment of classic or endemic KS skin lesions in patients who are HIV negative.

METHODS: We conducted a prospective, open-label, single center, phase II clinical trial. Imiquimod cream was applied under occlusion 3 times a week for 24 weeks. The main efficacy end points were the safety of topical imiquimod and the overall clinical response in patients evaluated on the basis of modified AIDS Clinical Trials Group criteria at 36 weeks. The statistical analysis was based on the intent-to-treat data set.

RESULTS: Seventeen patients were enrolled. Eight (47%) presented objective overall clinical response (2 complete and 6 partial responses). Tumor progression was noted in 6 patients. The most frequent side effects were local itching and erythema, seen in 9 patients (53%).

LIMITATIONS: This was not a randomized placebo-controlled study and was restricted to a small number of patients.

CONCLUSION: Topical imiquimod 5% cream had antitumor activity in about half the patients with classic and endemic KS and was generally well tolerated.

Journal of American Academy of Dermatology