Cancer stem cells and tumor heterogeneity: Deciphering the role in tumor progression and metastasis.

Tumor heterogeneity, in principle, reflects the variation among different cancer cell populations. It can be termed inter- or intra-tumoral heterogeneity, respectively, based on its occurrence in various tissues from diverse patients or within a single tumor. The intra-tumoral heterogeneity is one of the leading causes of cancer progression and treatment failure, with the cancer stem cells (CSCs) contributing immensely to the same. These niche cells, similar to normal stem cells, possess the characteristics of self-renewal and differentiation into multiple cell types. Moreover, CSCs contribute to tumor growth and surveillance by promoting recurrence, metastasis, and therapeutic resistance. Diverse factors, including intracellular signalling pathways and tumor microenvironment (TME), play a vital role in regulating these CSCs. Although a panel of markers is considered to identify the CSC pool in various cancers, further research is needed to discriminate cancer-specific CSC markers in those. CSCs have also been found to be promising therapeutic targets for cancer therapy. Several small molecules, natural compounds, antibodies, chimeric antigen receptor T (CAR-T) cells, and CAR-natural killer (CAR-NK) cells have emerged as therapeutic tools for specific targeting of CSCs. Interestingly, many of these are in clinical trials too. Despite being a much-explored avenue of research for years, and we have come to understand its nitty-gritty, there is still a tremendous gap in our knowledge concerning its precise genesis and regulation. Hence, a concrete understanding is needed to assess the CSC-TME link and how to target different cancer-specific CSCs by designing newer tools. In this review, we have summarized CSC, its causative, different pathways and factors regulating its growth, association with tumor heterogeneity, and last but not least, discussed many of the promising CSC-targeted therapies for combating cancer metastasis.