Survivin is one of the rare proteins that is differentially expressed in normal and cancer cells and is directly or indirectly involved in numerous pathways required for tumor maintenance. It is expressed in almost all cancers and its expression has been detected at early stages of cancer. These traits make survivin an exceptionally attractive target for cancer therapeutics. Even with these promising features to be an oncotherapeutic target, there has been limited success in the clinical trials targeting survivin. Only recently it has emerged that survivin was not being specifically targeted which could have resulted in the negative clinical outcome. Also, focus of research has now shifted from survivin expression in the overall heterogeneous tumor cell populations to survivin expression in cancer stem cells as these cells have proved to be the major drivers of tumors. Therefore, in this review we have analyzed the expression of survivin in normal and cancer cells with a particular focus on its expression in cancer stem cell compartment. We have discussed the major signaling pathways involved in regulation of survivin. We have explored the current development status of various types of interventions for inhibition of survivin. Furthermore, we have discussed the challenges involving the development of potent and specific survivin inhibitors for cancer therapeutics. Finally we have given insights for some of the promising future anticancer treatments.

The physiological state of the tumor microenvironment (TME) plays a central role in cancer development due to multiple universal features that transcend heterogeneity and niche specifications, like promoting cancer progression and metastasis. As a result of their preponderant involvement in tumor growth and maintenance through several microsystemic alterations, including hypoxia, oxidative stress, and acidosis, TMEs make for ideal targets in both diagnostic and therapeutic ventures. Correspondingly, methodologies to target TMEs have been investigated this past decade as stratagems of significant potential in the genre of focused cancer treatment. Within targeted oncotherapy, nanomedical derivates—nanocarriers (NCs) especially—have emerged to present notable prospects in enhancing targeting specificity. Yet, one major issue in the application of NCs in microenvironmental directed therapy is that TMEs are too broad a spectrum of targeting possibilities for these carriers to be effectively employed. However, cancer stem cells (CSCs) might portend a solution to the above conundrum: aside from being quite heavily invested in tumorigenesis and therapeutic resistance, CSCs also show self-renewal and fluid clonogenic properties that often define specific TME niches. Further scrutiny of the relationship between CSCs and TMEs also points towards mechanisms that underly tumoral characteristics of metastasis, malignancy, and even resistance. This review summarizes recent advances in NC-enabled targeting of CSCs for more holistic strikes against TMEs and discusses both the current challenges that hinder the clinical application of these strategies as well as the avenues that can further CSC-targeting initiatives. Graphical abstract Central role of CSCs in regulation of cellular components within the TME

It is imperative to identify the mechanisms that confer stemness to the cancer cells for more effective targeting. Moreover, there are not many studies on the link between stemness characteristics and the immune response in tumours. Therefore, in the current study involving GBM, we started with the study of BIRC5 (one of the rare genes differentially expressed in normal and cancer cells) and CXCR4 (gene involved in the survival and proliferation of CSCs). Together, these genes have not been systematically explored. We used a set of 27 promoter methylated regions in GBM. Our analysis showed that four genes corresponding to these regions, namely EOMES, BDNF, HLA-A, and PECAM1, were involved with BIRC5 and CXCR4. Interestingly, we found EOMES to be very significantly involved in stemness and immunology and it was positively correlated to CXCR4. Additionally, BDNF, which was significant in methylation, was negatively correlated to BIRC5.

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Glioblastoma multiforme (GBM) cancer stem cells (GSCs) are one of the strongest contributing factors to treatment resistance in GBM. Identification of biomarkers capable of directly affecting these cells within the bulk tumor is a major challenge associated with the development of new targeting strategies. In this study, we focus on understanding the potential of the multifunctional extraordinaire survivin as a biomarker for GSCs. We analyzed the expression profiles of this gene using various publicly available datasets to understand its importance in stemness and other cancer processes. The findings from these studies were further validated using human GSCs isolated from a GBM cell line. In these GSCs, survivin was inhibited using the dietary phytochemical piperine (PIP) and the subsequent effects on stemness, cancer processes and Temozolomide were investigated. In silico analysis identified survivin to be one of the most significant differentially regulated gene in GSCs, in comparison to common stemness markers. Further validation studies on the isolated GSCs showed the importance of survivin in stemness, cancer progression and therapy resistance. Taken together, our study identifies survivin as a more consistent GSC marker and also suggests the possibility of using survivin inhibitors along with standard of care drugs for better therapeutic outcomes.