Notch4+ cancer stem‐like cells promote the metastatic and invasive ability of melanoma

Lin, Xian; Sun, Baocun; Zhu, Dongwang; Zhao, Xiulan; Sun, Ryan; Zhang, Yanhui; Zhang, Danfang; Dong, Xueyi; Gu, Qing; Li, Yanlei; Liu, Fang

doi:10.1111/cas.12978

Cited by 47 publications

(44 citation statements)

References 57 publications

(62 reference statements)

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“…For example, CSCs of breast tumor are involved in spontaneous metastases in mouse models 6 . Moreover, CSCs promote the metastatic and invasive ability of melanoma 7 and their prsence is correlated with invasive behavior at colorectal adenocarcinoma 8 . The effect of the number of CSCs on tumor morphology has been the subject of several experimental studies and simulation.…”

Section: Introductionmentioning

confidence: 99%

Role of the Interplay Between the Internal and External Conditions in Invasive Behavior of Tumors

Azimzade

Saberi

Sahimi

2018

Sci Rep

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Tumor growth, which plays a central role in cancer evolution, depends on both the internal features of the cells, such as their ability for unlimited duplication, and the external conditions, e.g., supply of nutrients, as well as the dynamic interactions between the two. A stem cell theory of cancer has recently been developed that suggests the existence of a subpopulation of self-renewing tumor cells to be responsible for tumorigenesis, and is able to initiate metastatic spreading. The question of abundance of the cancer stem cells (CSCs) and its relation to tumor malignancy has, however, remained an unsolved problem and has been a subject of recent debates. In this paper we propose a novel model beyond the standard stochastic models of tumor development, in order to explore the effect of the density of the CSCs and oxygen on the tumor’s invasive behavior. The model identifies natural selection as the underlying process for complex morphology of tumors, which has been observed experimentally, and indicates that their invasive behavior depends on both the number of the CSCs and the oxygen density in the microenvironment. The interplay between the external and internal conditions may pave the way for a new cancer therapy.

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Section: Introductionmentioning

confidence: 99%

Role of the Interplay Between the Internal and External Conditions in Invasive Behavior of Tumors

Azimzade

Saberi

Sahimi

2018

Sci Rep

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“…Since NOTCH2 has been previously reported to promote proliferation and invasion in uveal melanoma [ 88 ], and also serves as a promising prognostic biomarker for oesophageal squamous cell carcinoma [ 89 ], it may play a pivotal role in maintaining derailed growth and invasiveness of melanoma cells. On the other hand, given that NOTCH4 signaling can either trigger EMT [ 90 ] or induce a MET-like phenotype [ 91 ] in certain melanoma settings, WM-266-4 cells could consist of EMT-subjected, tumor-initiating (TI; NOTCH4 + ) and MET-captured, metastatically-colonized (MC; NOTCH4 + ) sub-populations. Interestingly, DLL3 can operate as an inhibitor of NOTCH activity when both ligand and receptor are expressed in the same cell (“ in cis ”) [ 92 – 94 ], while DLL3 increased expression seems to essentially contribute to neuroendocrine tumorigenesis in vivo [ 95 ].…”

Section: Resultsmentioning

confidence: 99%

Deep-proteome mapping of WM-266-4 human metastatic melanoma cells: From oncogenic addiction to druggable targets

et al. 2017

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Cutaneous melanoma is a malignant tumor of skin melanocytes that are pigment-producing cells located in the basal layer (stratum basale) of epidermis. Accumulation of genetic mutations within their oncogenes or tumor-suppressor genes compels melanocytes to aberrant proliferation and spread to distant organs of the body, thereby resulting in severe and/or lethal malignancy. Metastatic melanoma’s heavy mutational load, molecular heterogeneity and resistance to therapy necessitate the development of novel biomarkers and drug-based protocols that target key proteins involved in perpetuation of the disease. To this direction, we have herein employed a nano liquid chromatography-tandem mass spectrometry (nLC-MS/MS) proteomics technology to profile the deep-proteome landscape of WM-266-4 human metastatic melanoma cells. Our advanced melanoma-specific catalogue proved to contain 6,681 unique proteins, which likely constitute the hitherto largest single cell-line-derived proteomic collection of the disease. Through engagement of UNIPROT, DAVID, KEGG, PANTHER, INTACT, CYTOSCAPE, dbEMT and GAD bioinformatics resources, WM-266-4 melanoma proteins were categorized according to their sub-cellular compartmentalization, function and tumorigenicity, and successfully reassembled in molecular networks and interactomes. The obtained data dictate the presence of plastically inter-converted sub-populations of non-cancer and cancer stem cells, and also indicate the oncoproteomic resemblance of melanoma to glioma and lung cancer. Intriguingly, WM-266-4 cells seem to be subjected to both epithelial-to-mesenchymal (EMT) and mesenchymal-to-epithelial (MET) programs, with 1433G and ADT3 proteins being identified in the EMT/MET molecular interface. Oncogenic addiction of WM-266-4 cells to autocrine/paracrine signaling of IL17-, DLL3-, FGF(2/13)- and OSTP-dependent sub-routines suggests their critical contribution to the metastatic melanoma chemotherapeutic refractoriness. Interestingly, the 1433G family member that is shared between the BRAF- and EMT/MET-specific interactomes likely emerges as a novel and promising druggable target for the malignancy. Derailed proliferation and metastatic capacity of WM-266-4 cells could also derive from their metabolic addiction to pathways associated with glutamate/ammonia, propanoate and sulfur homeostasis, whose successful targeting may prove beneficial for advanced melanoma-affected patients.

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“…Similar to mesenchymal stem cells, which are capable of tubulogenesis in vitro [ 262 ], it appears that some aggressively growing tumor cells can phenotypically mimic or transdifferentiate into several of these cell types, e.g., they can adopt features of ECs [ 173 , 174 ], pericytes [ 263 , 264 ], and even platelets [ 265 , 266 , 267 ]. In initiation of VM, both EMT and tumor-initiating cancer stem-like cells (CSCs) play important roles [ 149 , 268 , 269 ]. In glioblastoma, a portion of the tumor vasculature arises from CSCs which have been reported to differentiate to tumor vessel pericytes upon CXCL12/CXCR4 and TGFβ signaling [ 263 ].…”

Section: Tumor Cells Imitating Endothelial Cells In Vasculogenic Mmentioning

confidence: 99%

“…Nodal plays an essential role in VM such as in embryonic/stem cell differentiation as demonstrated by an impaired VM of aggressive melanoma cells upon downregulation of Nodal [ 174 , 316 ]. Notch 1 triggers EMT in hepatocellular carcinoma and promotes VM [ 317 ], while Notch4 is highly expressed in melanoma CSCs, where it promotes metastasis via the TWIST/VE-cadherin/E-cadherin pathway [ 269 ].…”

Section: Tumor Cells Imitating Endothelial Cells In Vasculogenic Mmentioning

confidence: 99%

Collateral Damage Intended—Cancer-Associated Fibroblasts and Vasculature Are Potential Targets in Cancer Therapy

Cavaco

Rezaei

Niland

et al. 2017

IJMS

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After oncogenic transformation, tumor cells rewire their metabolism to obtain sufficient energy and biochemical building blocks for cell proliferation, even under hypoxic conditions. Glucose and glutamine become their major limiting nutritional demands. Instead of being autonomous, tumor cells change their immediate environment not only by their metabolites but also by mediators, such as juxtacrine cell contacts, chemokines and other cytokines. Thus, the tumor cells shape their microenvironment as well as induce resident cells, such as fibroblasts and endothelial cells (ECs), to support them. Fibroblasts differentiate into cancer-associated fibroblasts (CAFs), which produce a qualitatively and quantitatively different extracellular matrix (ECM). By their contractile power, they exert tensile forces onto this ECM, leading to increased intratumoral pressure. Moreover, along with enhanced cross-linkage of the ECM components, CAFs thus stiffen the ECM. Attracted by tumor cell- and CAF-secreted vascular endothelial growth factor (VEGF), ECs sprout from pre-existing blood vessels during tumor-induced angiogenesis. Tumor vessels are distinct from EC-lined vessels, because tumor cells integrate into the endothelium or even mimic and replace it in vasculogenic mimicry (VM) vessels. Not only the VM vessels but also the characteristically malformed EC-lined tumor vessels are typical for tumor tissue and may represent promising targets in cancer therapy.

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Notch4+ cancer stem‐like cells promote the metastatic and invasive ability of melanoma

Cited by 47 publications

References 57 publications

Role of the Interplay Between the Internal and External Conditions in Invasive Behavior of Tumors

Role of the Interplay Between the Internal and External Conditions in Invasive Behavior of Tumors

Deep-proteome mapping of WM-266-4 human metastatic melanoma cells: From oncogenic addiction to druggable targets

Collateral Damage Intended—Cancer-Associated Fibroblasts and Vasculature Are Potential Targets in Cancer Therapy

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