Cervical Cancer Stem Cells and Their Association with Human Papillomavirus: Are They Ready as Anticancer Targets?

Abstract

Despite well-established human papillomavirus (HPV)-mediated etiology of cervical cancer, it has remained a major cause of cancer-related mortality of women from developing countries. Factors that contribute to high mortality rate primarily include disease diagnosis in advanced stages and failure of conventional treatment offered to these patients resulting in tumor relapse. Cancer stem cells (CSCs), in spite of controversies on their existence, are emerging as important players that initiate and maintain the tumor phenotype, govern tumor relapse, and chemo-/radioresistance, and thus considered as main factor that decides the treatment outcome. Recent studies provide evidence not only for presence of CSCs but also involvement of stemness-related signaling pathways and transcription factors in cervical cancer tissues and cell lines. The investigations made till date, however, lack evidence demonstrating a direct involvement of HPV oncoprotein(s) in modulation of CSC properties, relative proportions, or stem cell signaling in tumor tissues. Available literature, however, does support the involvement of HPV in these events. In the present article, we attempt to collate available data that demonstrates presence of CSC in cervical cancer, specific markers used to derive cervical CSC, and explored possibility of a potential cross talk of HPV oncoproteins with CSC signaling particularly with the known self-renewal signaling pathways like Notch, Hedgehog (Hh), and Wnt as well as stemness-related transcription factor like Oct4, Nanog, Sox2, and STAT3 that maintain CSC phenotype and functionality. Overall, present article provides rationale for detailed investigation of HPV role in regulation of CSC in cervical tumor tissues for an effective targeting of refractory lesions and to prevent tumor relapse.