Human bcl-2 Expression, Cleaved Caspase-3, and KSHV LANA-1 in Kaposi Sarcoma Lesions

Suzane Ramos da Silva, MSc; Maura M. Bacchi, MD; Carlos E. Bacchi, MD; Deilson Elgui de Oliveira, PhD

Disclosures

Am J Clin Pathol. 2007;128(5):794-802. 

In This Article

Abstract and Introduction

We aimed to evaluate the frequency of Kaposi sarcoma (KS).associated herpesvirus (KSHV) infection in KS lesions in patients from Brazil. In addition, expression of human bcl-2, cleaved caspase-3, and KSHV latency-associated nuclear antigen (LANA)-1 in tumors was evaluated using immunohistochemical analysis. We studied 64 KS cases, classified as follows: classical, 20 (31%); iatrogenic, 2 (3%); AIDSassociated, 25 (39%); and not otherwise specified (lack of information about HIV status), 17 (27%). KSHV was detected by polymerase chain reaction (PCR) in 61 cases (95%); 40 cases (63%) were KSHV+ by PCR and immunohistochemical analysis for LANA-1. Immunoexpression of bcl-2 was detected in 47 cases (73%). Only a few cells in 15 cases (23%) of KS had demonstrable immunostaining for cleaved caspase-3. These results further support the association of KSHV with all KS forms. Cleaved caspase-3 in KS tumors was infrequent, which may reflect the inhibition of apoptosis owing to bcl-2 overexpression observed in the majority of KS tumors.

In 1872, Moritz Kaposi[1] described a rare and indolent angiosarcoma that manifested mainly as skin lesions in elderly men.[2] Since the 1980s, Kaposi sarcoma (KS) has become a critical health issue with the emergence of AIDS epidemics.[2] AIDS-associated KS is an aggressive form of KS that shows widespread skin and mucosal lesions and occurs predominantly in homosexual and bisexual men.[3]

Besides classical KS and AIDS-associated KS, 2 other clinical-epidemiologic forms of KS are known:[4] endemic KS, which affects children and young men in central Africa;[5] and iatrogenic KS, observed in patients receiving immunosuppressive therapy.[4,6,7] It is noteworthy that KS lesions may regress when immunosuppressive treatment is discontinued, suggesting that tumor development is influenced by the efficiency of the immune response. This hypothesis is further supported by data that show high KS frequency in HIV+ people. Indeed, KS is at least 20,000 times more common in people with AIDS than in the general population and 300 times more common than in other immunosuppressed groups.[8]

The main component of KS lesions is a group of spindleshaped cells accompanied by a variable number of abnormal blood vessels, hemorrhage, and inflammatory cells. Like endothelial cells, the spindle-shaped cells in KS secrete and can be stimulated by angiogenic factors, including vascular endothelial growth factor (VEGF), thus contributing to the abundant vascular proliferation observed in KS lesions. Morphologically, mucocutaneous KS may manifest as early macular patch lesions to thickened or indurated papules and plaques, which ultimately form tumors.[4,9,10]

In 1994, Chang et al[11] identified unique herpesvirus DNA sequences in KS lesions from HIV+ patients and detected Kaposi sarcoma.associated herpesvirus (KSHV), or human herpesvirus type 8, in 93% of 27 cases. KSHV has been detected in all epidemiologic KS forms and in a few lymphoid tumors.[2]

The KSHV genome encodes several products with putative oncogenic properties, including some that share structural and functional homology with human proteins. KSHV oncoproteins interfere with critical processes, including cell proliferation, signal transduction, and apoptosis. The latencyassociated nuclear antigen (LANA)-1 protein impairs the activity of p53 and pRb tumor-suppressing proteins[12,13] and increases the expression of interleukin-6, an important growth factor for KS-infected cells.[14] LANA-1 also enhances HIV-1 tat function and activates the viral long terminal repeat, increasing the HIV-1 viral load.[15]

Cell death by apoptosis is an important process required for normal development and maintenance of tissue homeostasis. Apoptosis can be triggered by an intrinsic mitochondriadependent or extrinsic death receptor.mediated pathway. Both result in the proteolytic activation of procaspase-3, which drives the activation of other executioner caspases that cause cellular collapse. Caspase-3 itself is responsible for some features observed in apoptotic cells, including plasmatic membrane blebbing, DNA degradation, and nuclear fragmentation.[16,17]

Overexpression of some antiapoptotic proteins has prognostic value in some human cancers.[18,19] Remarkably, human bcl-2 inhibits apoptosis, directly by binding Apaf-1, thus preventing the activation of caspases cascade, or indirectly by decreasing the availability of cytochrome c in cell cytoplasm.[20,21,22] Indeed, bcl-2 overexpression has been observed in prostate cancer, breast cancer, non.small cell lung cancer, small cell lung cancer, and melanoma.[23]

There are insufficient data on the value of apoptosis in KS pathogenesis and on the frequency of the expression of antiapoptotic proteins in malignant cells.[24,25] Thus, we aimed to evaluate the frequency of KSHV in patients with KS from among HIV+ and HIV. patients from Brazil and to study the expression of human bcl-2, cleaved caspase-3, and KSHV LANA-1 in KS lesions.

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