Cancer stem cells and ceramide signaling: the cutting edges of immunotherapy
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REVIEW
Cancer stem cells and ceramide signaling: the cutting edges of immunotherapy Sweta Ghosh1 · Subir Kumar Juin1 · Subrata Majumdar1 Received: 3 April 2020 / Accepted: 28 August 2020 © Springer Nature B.V. 2020
Abstract The multipotent, self renewing “cancer stem cells” (CSCs), a small population within tumor microenvironment facilitates transformed cells to grow and propagate within the body. The CSCs are discovered as resistant to the chemotherapeutic drug with distinct immunological characteristics. In recent years, immunologically targeting CSCs have emerged as an integral part of effective and successful cancer therapy. CSCs notably exhibit dysregulation in conventional sub-cellular sphingolipid metabolism. Recently, ceramide decaying enzymes have been shown to activate alternative ceramide signaling pathways leading to reduction in efficacy of the chemotherapeutic drugs. Therefore, a control over ceramide mediated modulations of CSCs offers an attractive dimension of effective cancer treatment strategy in future. In this review, we focused on the recent findings on broad spectrum of ceramide mediated signaling in CSCs within the tumor niche and their role in potential cancer immunotherapy. Keywords Cancer stem cell · Ceramide · Glucosylceramide synthase · Multidrug resistance · Hypoxia · Immunotherapy
Introduction Cellular heterogeneity within tumor microenvironment (TME) is a hallmark of cancer. Malignancy depends on a heterogeneous, small subset of rare immortal cells termed as cancer stem cells (CSCs) or tumor initiating cells [1]. Such rare subpopulation of cancer initiating cells has the capacity to self-renew and differentiate into clonal cancer cells. CSCs within a tumor microenvironmental niche are the seeds of tumorigenesis and these CSCs are designated as the real driving force behind tumor recurrences after clinical abrogation of cancer [2, 3]. Furthermore, CSCs are differentiated into various cell types that constitute the tumor and help in the formation of an adverse neoplastic condition. CSCs mediated deformation in cellular metabolism and stimulation of angiogenesis depends on low oxygen tensions i.e., hypoxia [4]. CSCs with their unique properties are identified by the expression of a distinct set of protein markers [5, 6]. Human CSCs are reported to be present in solid tumors, while as few as one hundred CSCs are capable of generating * Subrata Majumdar [email protected] 1
Division of Molecular Medicine, Bose Institute, P‑1/12, CIT Scheme VII M, Kolkata 700054, India
malignant tumors in non-obese diabetic/severe combined immunodeficient (NOD/SCID) mice [7]. Several human cancers have been reported to be enriched with CSCs including breast cancer, brain cancer, glioblastoma, colon cancer, lung cancer, melanoma, prostate cancer and pancreatic cancer [7–10]. Cell surface proteins like CD133, CD44, CD24, CD166, epithelial-specific antigen (ESA), CD29, CD34 and EpCAM, transcription factors like Oct-4 and Sox2, ATPbinding cassette (ABC) transporters like ABCG2, enzymes like Ald
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