Philippe Hermans

Iron as a potential co-factor in the pathogenesis of Kaposi's sarcoma?

The role of iron in the pathogenesis of several tumours is being increasingly investigated. In particular, its involvement in the pathogenesis of Kaposis sarcoma (KS) is suggested by the distribution of the endemic form of KS corresponding to continental rifts and associated iron‐oxide‐rich volcanic clays. We investigated in vitro to what extent iron supplementation or withdrawal could affect the growth of KS‐derived cells, by analysing the effects of adding iron salts (iron chloride and ferric nitrilotriacetate) and/or reducing iron by iron chelators (desferrioxamine) on KS‐derived cell cultures. The addition of iron salts strongly stimulated the growth of KS cells, as reflected by increase in thymidine incorporation and cell number. Conversely, desferrioxamine and deferiprone inhibited cell growth. The inhibitory effect of iron chelation was more pronounced on rapidly dividing basic fibroblast‐growth‐factor‐stimulated cells. These results may point to a novel therapeutic approach to KS. Int. J. Cancer 78:720–726, 1998.

p53 protein overexpression is a common but late event in the pathogenesis of iatrogenic and AIDS-related Kaposi’s sarcoma

Kaposi’s sarcoma (KS) is characterized by microvascular proliferation (angiogenesis) in the initial stage of lesion development that is soon followed by the proliferation of spindle-shaped cells which are considered to be the KS ‘tumor’ cells [1]. Despite intensive research over the past few years, the pathogenesis of KS remains unclear, and it is not known whether KS is a true neoplasm, since it shows multicentric origin, frequent regression and normal karyotypes. The latest hypotheses suggest that KS results from a multistep pathway involving cytokine dysregulation, the presence of HIV and/or human herpesvirus 8, overexpression of integrins and resistance to apoptosis [2–6]. Recently, one of the best known proteins involved in the regulation of cell growth, the p53 protein, has been suggested to play a role in the pathogenesis of KS. Indeed, mutations of the p53 gene have been detected in up to 29% of KS [7]. The loss of p53 function, by allelic loss or by mutations of its corresponding gene, has been shown to result in increased cell proliferation or in defective apoptosis in numerous human cancers [8]. In this study, we investigated iatrogenic and AIDS-related KS for the presence of p53 alterations in correlation with the different progressive histological stages (patch, plaque and nodular). Routinely processed, formalin-fixed and paraffin-embedded tissue samples of KS were obtained from patients with AIDS (n = 37) and from renal transplant recipients receiving immunosuppressive therapy (n = 6). All samples were classified according to their histological stage, as described elsewhere [1] (patch stage, 17 cases; plaque or nodular stages, 26 cases). p53 accumulation was detected immunohistochemically with the monoclonal antibody DO7 (Dako, Glostrup, Denmark) which recognizes both wild-type and mutant p53 [9]. Immunohistochemistry was performed using the antigen retrieval method as previously described [10]. All the 26 plaque or nodular stage KS samples (‘late KS’) displayed p53 immunoreactivity (100%) whereas only three patch stage KS (‘early KS’) showed p53 imJ.-C. Noel · F. De Thier · Th. Simonart · J. Andre · P. Hermans · J. P. Van Vooren · M. Heenen

Phenotypic characteristics of Kaposi's sarcoma tumour cells derived from patch-, plaque- and nodular-stage lesions: analysis of cell cultures isolated from AIDS and non-AIDS patients and review of the literature: KAPOSI's SARCOMA PHENOTYPE

Background u2002Kaposis sarcoma (KS) is commonly thought to be derived from endothelial cells because of the predominant expression of endothelial markers in KS lesions. However, the heterogeneity of the spindle‐cell compartment makes the precise lineage relationship of KS tumour cells unclear. Cultured KS‐derived spindle cells constitutively overexpress antiapoptotic proteins and exhibit invasive properties, which suggests that they may adequately represent the tumour cells of KS. Objectivesu2002We aimed to investigate the expression of a wide variety of immunohistochemical markers by spindle cells derived from patch‐, plaque‐ and nodular‐stage lesions from patients with iatrogenic, sporadic and acquired immune deficiency syndrome‐related KS, and to review the data reported by other laboratories. Methodsu2002Cells from six KS cell cultures derived from four subjects were examined by immunostaining. Resultsu2002Comparison of these data indicates that KS‐derived spindle cells generally express myofibroblast antigens but lack endothelial and/or leucocyte markers. Conclusionsu2002As the myofibroblast phenotype is not the predominant feature of KS tissues, our findings further substantiate the view that the in vivo dominant endothelial population represents a reactive hyperplasia rather than the true KS tumour process.

Cultured Kaposi's sarcoma tumor cells exhibit a chemokine receptor repertoire that does not allow infection by HIV-1

BackgroundHIV-1 is known to play a critical role in the pathogenesis of AIDS-associated Kaposis sarcoma (KS). However, it remains controversial whether KS cells are target cells for HIV infection. The aim of this study was to investigate the expression of chemokine receptors in KS cell cultures and to determine whether these cells can be infected by HIV-1.Material and MethodsKS-derived cells and KS-Y1 cells were investigated using RT-PCR for the expression of CD4, CCR3, CCR5, CCR8 and CXCR4 mRNA. HIV infectivity of these cells was determined by p24 antigen and HIV-1 RNA production, as well as by HIV-1 DNA integration.Results and DiscussionWith the exception of CCR8 which is expressed by KS-derived spindle cell cultures but not by KS-Y1 cells, unstimulated KS cells express no significant levels of CD4, CCR3, CCR5 or CXCR4 mRNA. HIV infectivity assays showed that KS cells were unpermissive to HTLVIIIB and JRFL strains. Although the expression of CXCR4 mRNA could be upregulated by interleukin-1β, stimulation of KS cells by this cytokine did not allow infection by HIV-1.ConclusionsThis shows that KS cells exhibit a chemokine receptor repertoire that does not allow infection by HIV-1. Other cell types making up KS lesions, such as inflammatory cells, are likely to represent the source of HIV-1 products cooperating to promote KS development and progression.

PCR assay fails to detect molluscum contagiosum virus-related sequences in AIDS-related Kaposi's sarcoma

Previous PCR-based studies have demonstrated the presence of various viral DNA or RNA sequences in Kaposis sarcoma (KS) tissues. To date, only human herpesvirus 8 (HHV-8) DNA sequences are found consistently in KS. The putative role of this agent in KS pathogenesis remains, however, to be determined; HHV-8 could infect populations endemically and could be reactivated in patients with KS. A close association between AIDS-related KS and molluscum contagiosum occurrence was found and this study was conducted primarily to search for the presence of molluscum contagiosum virus DNA sequences in KS. Frozen KS samples were examined for the presence of both HHV-8 and molluscum contagiosum virus DNA sequences by PCR. Despite a high rate of co-infection, no molluscum contagiosum virus (MCV) DNA sequence could be found in the KS samples whereas HHV-8 was uniformly detected. These results suggest that the high prevalence of MCV in AIDS patients with KS relies on a mode of transmission common for HHV-8 and molluscum contagiosum virus rather than on a multiviral etiology of KS. They may also indicate a particular susceptibility of the host to viral reactivation. If this is so, the failure to detect MCV DNA sequences in KS tissues by PCR indicates that locally produced or released cyotokines are not involved in the latter process.

Human herpesvirus 8 investigations: A role in the clinical management of Kaposi's sarcoma?

Kaposi’s sarcoma (KS) is a vascular tumour associated with infection by human herpesvirus 8 (HHV-8). Most of the recent studies on KS have focused on the epidemiology and molecular biology of HHV-8. However, the contribution of virological investigations into HHV-8 to the clinical management of KS has been poorly evaluated so far. From a diagnostic point of view, HHV-8 currently appears as a useful tool for distinguishing KS from its mimics. Seroconversion to antibodies against HHV-8 may predict the development of KS in susceptible individuals, and reduction of HHV-8 viraemia is associated with therapies effective against KS. Further prospective studies are still required to determine the role of serological or genotypic investigations into HHV-8 in the prevention of KS and in KS response to therapy.

Penile intraepithelial neoplasia overlying Kaposi's sarcoma lesions: Role of viral synergy?

Several viral agents have been detected in the lesional tissue of Kaposis sarcoma (KS). Their precise oncogenic role remains to be determined. A 32-year-old heterosexual man with acquired immunodeficiency syndrome (AIDS) who had penile lesions of KS with overlying epithelial changes characteristic of intraepithelial neoplasia associated with concurrent infection by human papillomavirus (HPV) and human herpesvirus 8 (HHV-8) is reported. The absence of viral DNA from uninvolved skin suggests that this coinfection is more than coincidental and may involve synergy between these viruses, as has already been suggested for HPV and herpes simplex 2 virus.

Stimulation of Kaposi's sarcoma cell growth by urine from women in early pregnancy, the current source for clinical-grade human chorionic gonadotropin preparations.

Abstract: Clinical‐grade preparations of human chorionic gonadotropin (hCG) have been shown to be toxic to Kaposis sarcoma (KS) cells. However, the results of clinical studies using commercial hCG preparations KS remain highly contradictory. More particularly, some hCG preparations could have a paradoxical growth effect on KS. Such discrepant results may be explained by the fact that the anti‐KS activity is not associated with hCG itself but with one or more factors that are co‐purified with the hormone. We found here that crude urine from first trimester pregnant women, the current source for commercial hCG, had a growth stimulatory effect on KS cells. By contrast, urine from last trimester pregnant women, from non‐pregnant young women, from menopausal women and from men exhibited neither a growth stimulatory nor a growth inhibitory effect on KS cells. The amplitude of this pregnancy urine‐associated pro‐KS activity/hCG unit was higher than that achieved with clinical‐grade hCG preparations. Partial co‐purification of pregnancy‐associated factors during the extraction procedure of commercial hCG from urine may explain the pro‐KS activity achieved with some hCG preparations. We, therefore, suggest a cautious use of hCG purified from pregnancy urine for the treatment of KS.