Angiogênese, células-tronco neoplásicas CD34+ e sinvastatina em modelo de carcinogênese mamária induzida quimicamente / Angiogenesis, CD34+ cancer stem-cells and simvastatin in a chemically induced mammary carcinogenesis model
AUTOR(ES)
Marcos José Alves Junior
FONTE
IBICT - Instituto Brasileiro de Informação em Ciência e Tecnologia
DATA DE PUBLICAÇÃO
20/02/2012
RESUMO
Breast cancer is the most common malignancy and the leading cause of death from cancer among females worldwide. Despite all the research and all the progress achieved so far, the morbidity and mortality due to this cancer remains high in patients at advanced stages. Recently, it was described a new model of carcinogenesis in which stem cells (SC) could be responsible for the origin, morphological heterogeneity and self-renewal of cancer. In support of this theory, it has been observed, in most solid tumors, the presence of cells showing phenotypic and biological characteristics of stem cells, which have thus been designated cancer stem cells (CSC). Being associated with therapeutic resistance and tumor recurrence in the long run, CSCs constitute an important target in pharmacological and pathophysiological studies. In addition to CSCs, promising therapeutical targets also include tumor angiogenesis. Nevertheless, very few studies have focused on the interrelations of these two strategies. Statins are first-line anti-dyslipidemic drugs which have been shown to possess anti-neoplastic properties - possibly related to anti-apoptotic and/or anti-angiogenic effects (although these putative mechanisms have not yet been entirely investigated). Based on preliminary results of Gauthaman et al. (in vitro data) and of our group (in vivo data), indicating that statins (specially the lipophilic ones) may have a specific inhibitory effect over mammary CSCs, we sought to elucidate the in vivo effect of simvastatin on tumor angiogenesis and CD34+ CSC, simultaneously; this was achieved using a well-recognized carcinogenesis model, where a single dose of 7,12-Dimethylbenz(a)anthracene (DMBA) is used to induce of mammary tumors in Sprage-Dawley female rats. Of notice, this is the first time angiogenesis is quantitatively and morphologically assessed in this model. Our results show that simvastatin significantly increases the relative participation of invasive ductal carcinoma as a subcomponent of the induced mixed tumors, suggesting that this drug may modulate the morphologic plasticity of DMBA-induced mammary neoplasms. It was also observed a significant reduction in the microvessel density (MVD) of treated tumor tissue, when compared to that of untreated specimens. No significant difference was seen in terms of CD34+CSC number, when comparing treated and untreated tissues, which is in clear contrast to in vitro results reported in the literature and to our own in vivo results (using other CSC markers). In conclusion, in the present protocol, simvastatin, at the dose of 40mg/kg daily for 14 days (which is comparable to the anti-dyslipidemic doses used in humans), has anti-angiogenic and morphologic effects on DMBA-induced mammary tumors, but no significant action on CD34+ CSCs.
ASSUNTO(S)
neovascularização patológica células-tronco neoplásicas sinvastatina antígenos cd34 imunohistoquímica neovascularization pathologic neoplastic stem cells simvastatin antigens cd34 immunohistochemistry
