Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF. These nuclear events require, in a first step, displacement of the corepressor Groucho (9) and, subsequently, recruitment of the histone acetylase CREB-binding protein (CBP)/p300 and coactivators, like pygopus (PYG) and BCL9 (10). 2011;481:85. Vascular channel formation by human melanoma cells in vivo and in vitro: vasculogenic mimicry. Oncogene. Therapeutic resistance and tumor resilience and recurrence are all intrinsically linked to tumor heterogeneity and microenvironmental crosstalk. The cancer stem cell niche—there goes the neighborhood? Hypoxia-inducible factor-1 modulates gene expression in solid tumors and influences both angiogenesis and tumor growth. Note that further information is provided in the notes section for each slide. While it remains to be determined the extent of the overlap between these tissues specific metastatic program to the expression profile of CSCs, evidence have shown that metastatic cancer possess distinct stem-like gene expression signatures [161,162,163]. This quiescence-associated resistance also implies the temporal nature of CSC enrichment, in addition to different molecular mechanisms and therefore requiring a careful strategy to develop the therapy. Subsequently, progression of the metastasis outgrowth is potentiated by the cellular and molecular component of the metastatic niche. For example, imbalance of intestinal and hematopoietic homeostasis is a predictable bystander effect of nonspecific Wnt inhibition (40). Differentiated tumor progeny represents the majority of most tumors, relative to CSCs (. 2013;8:e62493. 2014;234:11–22. The presence of stem cell in cancer were further supported in other studies in breast cancer [12], brain [13] and subsequently other types of cancers. 2006;17:3–14. Nat Rev Cancer. Initiation of cancer by CSCs is prominent due to their stemness properties allowing them to accumulate the underlying carcinogenic and mutagenic inducer including inflammation and oxidative stress. Oncotarget. Terms and Conditions, Due to their having the self-renewal capacity and differentiation capacity in driving the tumour growth, CSCs are hypothesised to be originated from the normal stem cells/progenitor cells of the tumour tissues. 2013;56:326–33. 2017;66:102–15. Identification and expansion of human colon-cancer-initiating cells. Proc Natl Acad Sci. Prospective identification of tumorigenic breast cancer cells. In a report by Lee et al., treatment with chemotherapy drugs induced adaptive drug resistance and increased CXCR4high cells with metastatic potential in ovarian cancer cell lines, whereas removal of drugs causes the cells to revert the state transition. Until the recent years, many studies are emerging to elucidate the metabolic landscape in CSC, as metabolic reprogramming/switch may have a vital role in the acquisition of stemness, therefore conferring their resistance mechanisms. Other than the cellular component, the tumour microenvironment also comprises of non-cellular component that maintains the behaviour of the malignancy, which is the ECM. Genetic background is an important determinant of metastatic potential. Checkpoint inhibitors such as PD-L1 or PD-1 antagonists (e.g., nivolumab and atezolizumab) have been used to target the bulk tumor of many solid cancers, but CSC-specific strategies may require the characterization and targeting of additional immunosuppressive or checkpoint mechanisms. CSCs are defined as cells that are endowed with both self-renewal and multilineage differentiation potential (4, 5) and, as such, are believed to clonally expand and repopulate the various types of differentiation lineages present within the tumor. However, if the hypothesis of CSC being resistant population of cells is accepted, it may be possible that these cells are either; i) quiescent, non-dividing cells hence conferring their insensitivity, or ii) proliferative CSCs, but insensitive to the chemotherapy due to activation of resistance mechanisms. Cytokine signaling, for example production of interleukin-6 (IL6) by endothelial cells, or interleukin-4 by CSCs, promotes CSC maintenance and immunosuppression, respectively. Tissue repair and stem cell renewal in carcinogenesis. Zhou W, Susan QK, Zhi H, William F, Xiaoguang F, Jeremy P, Ling W, Andrew ES, Roger EM, Xiaoxia L, Jeremy NR, Shideng. It is anticipated that drug design will require agents providing great specificity and a certain therapeutic window between normal stem cells and CSCs. MSC also promotes stemness through NF-κB pathways via secretion of CXCL12, IL-6, and IL-8 [30]. Human mesenchymal stem cells (hMSCs) target osteosarcoma and promote its growth and pulmonary metastasis. Emerging technologies are paving the way for a more integrated understanding of CSC-microenvironment interactions. Metabolic reprogramming may represent an important intrinsic CSC regulation and glycolytic inhibition may be an attractive strategy to target the CSCs. In 1989, the ‘seed and soil’ hypothesis for metastasis by Steven Paget’s established pivotal framework whereby both the intrinsic properties of the cancer cells i.e. In addition, inflammatory cells such as CD113b expressing myeloid cells and macrophages were also recruited leading to the formation pre-metastatic niche through increased expression of S100 calcium binding proteins following induction by TNFα, TGFβ and VEGFA secreted by primary tumour cells [168, 169]. 2006;444:756–60. PubMed Google Scholar. The acquisition of these aggressive phenotypes is prominently implicated by the acquisition of mesenchymal phenotypes through the epithelial mesenchymal transition (EMT) [134,135,136]. Aldehyde dehydrogenase activity of breast cancer stem cells is primarily due to isoform ALDH1A3 and its expression is predictive of metastasis. The main therapeutic modalities ; however, the coexistence of diverse microenvironments throughout a solid tumor generates and for... 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