Targeting self-renewal pathways in cancer stem cells: clinical implications for cancer therapy

Abstract

Extensive cancer research in the past few decades has identified the existence of a rare subpopulation of stem cells in the grove of cancer cells. These cells are known as the cancer stem cells marked by the presence of surface biomarkers, multi-drug resistance pumps and deregulated self-renewal pathways (SRPs). They have a crucial role in provoking cancer cells leading to tumorigenesis and its progressive metastasis. Cancer stem cells (CSCs) are much alike to normal stem cells in their self-renewal mechanisms. However, deregulations in the SRPs are seen in CSCs, making them resistant to conventional chemotherapeutic agents resulting in the tumor recurrence. Current treatment strategies in cancer fail to detect and differentiate the CSCs from their non-tumorigenic progenies owing to absence of specific biomarkers. Now, it has become imperative to understand complex functional biology of CSCs, especially the signaling pathways to design improved treatment strategies to target them. It is hopeful that the SRPs in CSCs offer a promising target to alter their survival strategies and impede their tumorigenic potential. However, there are many perils associated with the direct targeting method by conventional therapeutic agents such as off targets, poor bioavailability and poor cellular distribution. Recent evidences have shown an increased use of small molecule antagonists directly to target these SRPs may lead to severe side-effects. An alternative to solve these issues could be an appropriate nanoformulation. Nanoformulations of these molecules could provide an added advantage for the selective targeting of the pathways especially Hedgehog, Wnt, Notch and B-cell-specific moloney murine leukemia virus integration site 1 in the CSCs while sparing the normal stem cells. Hence, to achieve this goal a complete understanding of the molecular pathways corroborate with the use of holistic nanosystem (nanomaterial inhibition molecule) could possibly be an encouraging direction for future cancer therapy.

Preclinical and clinical implications of TERT promoter mutation in glioblastoma multiforme

“…Therefore, a significant association between TERT promoter mutation and the in vitro sphere-forming capacity of GBM cells, identified in the present study, suggests that mutations in the TERT promoter region are associated with the biology of GBM cells to enhance self-renewal capacity. Self-renewal capacity is a key feature of GBM cancer stem cells that exert recurrence following anti-cancer treatments (24,25). Therefore, TERT promoter mutations resulting in overexpression of TERT may be associated with treatment resistance of GBMs.…”

“…Previous studies have demonstrated the negative clinical impacts of TERT promoter mutation or longer telomere length in a number of types of cancer, including GBMs (15,20,21,25,26). TERT promoter mutations may generate novel binding motifs for E26 transformation-specific/T-cell factor transcription Table II.…”

Forced expression of Wnt antagonists sFRP1 and WIF1 sensitizes chronic myeloid leukemia cells to tyrosine kinase inhibitors

“…[1][2][3][4][5][6] Aberrant regulation of the Wnt signaling pathway is known to play a role in tumorigenesis and maintenance of cancer stem cells. 3,4,28 The Wnt pathway can be activated aberrantly not only by mutations of genes functioning in Wnt signaling such as APC and CTNNB1 but also by dysregulation of secreted antagonists. For example, diminished expression caused by promoter methylation of Wnt antagonists genes sFRP1 and WIF1 results in unregulated increase of ligand-dependent Wnt signaling activity.…”

Caracterização do efeito anti-neoplásico do butirato em duas linhagens celulares de rato derivadas de tumores hepáticos com diferente ní­vel de diferenciação

“…Já Embora o mecanismo não seja ainda conhecido, a inibição do Bmi-1 pode levar à inibição da proliferação e bloqueio da EMT (BORAH et al, 2015).…”

“…Esta via foi descrita inicialmente em Drosophila e foi associada com o desenvolvimento embrionário. Em muitas neoplasias, a atividade da via Hedgehog encontra-se aumentada, promovendo o crescimento celular e controlando aspetos das CSCs como a auto-renovação (BORAH et al, 2015). Neste sentido, um dos principais pontos de regulação da via é por meio do controle da proteína de membrana SMO (MERCHANT;MATSUI, 2010).…”