Efficient tumour formation by single human melanoma cells

Quintana, Elsa; Shackleton, Mark; Sabel, Michael S.; Fullen, Douglas R.; Johnson, Timothy M.; Morrison, Sean J.

doi:10.1038/nature07567

Cited by 1,644 publications

(1,572 citation statements)

References 40 publications

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“…We have chosen the most immunocompromised strain of mice, which is NOD/SCID/IL‐2R −/− (NSG), to neutralize the effect of PD‐L1 on the immune system. In this strain of mice the incidence of tumor formation was extremely high, which is consistent with previous reports 26. Even with this high level of tumorigenicity, knockdown of PD‐L1 resulted in ninefold decrease the frequency of CSCs from 1:1 in the control cells to 1:9 in the PD‐L1 knockdown cells (Table 1).…”

Section: Resultssupporting

confidence: 91%

PD‐L1 promotes OCT4 and Nanog expression in breast cancer stem cells by sustaining PI3K/AKT pathway activation

Almozyan

Çolak

Mansour

et al. 2017

Intl Journal of Cancer

193

120

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The expression of PD‐L1 in breast cancer is associated with estrogen receptor negativity, chemoresistance and epithelial‐to‐mesenchymal transition (EMT), all of which are common features of a highly tumorigenic subpopulation of cancer cells termed cancer stem cells (CSCs). Hitherto, the expression and intrinsic role of PD‐L1 in the dynamics of breast CSCs has not been investigated. To address this issue, we used transcriptomic datasets, proteomics and several in vitro and in vivo assays. Expression profiling of a large breast cancer dataset (530 patients) showed statistically significant correlation (p < 0.0001, r = 0.36) between PD‐L1 expression and stemness score of breast cancer. Specific knockdown of PD‐L1 using ShRNA revealed its critical role in the expression of the embryonic stem cell transcriptional factors: OCT‐4A, Nanog and the stemness factor, BMI1. Conversely, these factors could be induced upon PD‐L1 ectopic expression in cells that are normally PD‐L1 negative. Global proteomic analysis hinted for the central role of AKT in the biology of PD‐L1 expressing cells. Indeed, PD‐L1 positive effect on OCT‐4A and Nanog was dependent on AKT activation. Most importantly, downregulation of PD‐L1 compromised the self‐renewal capability of breast CSCs in vitro and in vivo as shown by tumorsphere formation assay and extreme limiting dilution assay, respectively. This study demonstrates a novel role for PD‐L1 in sustaining stemness of breast cancer cells and identifies the subpopulation and its associated molecular pathways that would be targeted upon anti‐PD‐L1 therapy.

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Section: Resultssupporting

confidence: 91%

PD‐L1 promotes OCT4 and Nanog expression in breast cancer stem cells by sustaining PI3K/AKT pathway activation

Almozyan

Çolak

Mansour

et al. 2017

Intl Journal of Cancer

193

120

View full text Add to dashboard Cite

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“…Recent reports, based on transplantation of a broad spectrum of both primary and xenografted melanomas, contradict those conclusions (Quintana et al, 2008;Boiko et al, 2010). In the study by Boiko et al, melanoma tumor stem cells were isolated using neural crest nerve growth factor receptor CD271, comprising between 2.5 and 41% (mean ¼ 16.7%) of the surgical patient melanoma samples and 6.4 and 75.3% (mean ¼ 26.3%) in xenografted tumors.…”

Section: Discussionmentioning

confidence: 99%

Trastuzumab (herceptin) targets gastric cancer stem cells characterized by CD90 phenotype

et al. 2011

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Identification and characterization of cancer stem cells (CSCs) in gastric cancer are difficult owing to the lack of specific markers and consensus methods. In this study, we show that cells with the CD90 surface marker in gastric tumors could be enriched under non-adherent, serumfree and sphere-forming conditions. These CD90 þ cells possess a higher ability to initiate tumor in vivo and could re-establish the cellular hierarchy of tumors from singlecell implantation, demonstrating their self-renewal properties. Interestingly, higher proportion of CD90 þ cells correlates with higher in vivo tumorigenicity of gastric primary tumor models. In addition, it was found that ERBB2 was overexpressed in about 25% of the gastric primary tumor models, which correlates with the higher level of CD90 expression in these tumors. Trastuzumab (humanized anti-ERBB2 antibody) treatment of hightumorigenic gastric primary tumor models could reduce the CD90 þ population in tumor mass and suppress tumor growth when combined with traditional chemotherapy. Moreover, tumorigenicity of tumor cells could also be suppressed when trastuzumab treatment starts at the same time as cell implantation. Therefore, we have identified a CSC population in gastric primary tumors characterized by their CD90 phenotype. The finding that trastuzumab targets the CSC population in gastric tumors suggests that ERBB2 signaling has a role in maintaining CSC populations, thus contributing to carcinogenesis and tumor invasion. In conclusion, the results from this study provide new insights into the gastric tumorigenic process and offer potential implications for the development of anticancer drugs as well as therapeutic treatment of gastric cancers.

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“…As little as one melanoma cell has been found to form a tumor when coinjected with BME into an immunocompromised mouse. 53 This demonstrates that even needle biopsies have the potential to yield tumors when coinjected with BME. The amount of BME protein is important.…”

Section: Dormancy Assaymentioning

confidence: 95%

Multiple uses of basement membrane‐like matrix (BME/Matrigel) in vitro and in vivo with cancer cells

Benton

Kleinman

George

et al. 2011

Intl Journal of Cancer

187

134

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Significant advances in our understanding of cancer cell behavior, growth, and metastasis have been facilitated by studies using a basement membrane-like extracellular matrix extract, also known as Matrigel. The basement membrane is a thin extracellular matrix that is found in normal tissues and contacts epithelial and endothelial cells, smooth muscle, fat, Schwann cells, etc. It is composed of mainly laminin-111, collagen IV, heparan sulfate proteoglycan, entactin/nidogen, and various growth factors (fibroblast growth factor, transforming growth factor beta, epidermal growth factor, etc.). Most tumors of epithelial origin produce significant amounts of basement membrane matrix and interact with it particularly during metastasis. Cancer cells metastasize via degradation of the vessel basement membrane matrix to extravasate into the blood stream and colonize distant sites. This review will focus on the interaction of cancer cells and cancer stem cells with the basement membrane-like matrix and the various uses of this interaction to accelerate tumor growth in vivo and to develop in vitro assays for invasion, morphology, and dormancy. Such assays and methods have advanced our understanding of the process of cancer progression, the genes and pathways that are involved, the potential of various therapeutic agents, the effects of neighboring cells, and the role of stem cells.

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Efficient tumour formation by single human melanoma cells

Cited by 1,644 publications

References 40 publications

PD‐L1 promotes OCT4 and Nanog expression in breast cancer stem cells by sustaining PI3K/AKT pathway activation

PD‐L1 promotes OCT4 and Nanog expression in breast cancer stem cells by sustaining PI3K/AKT pathway activation

Trastuzumab (herceptin) targets gastric cancer stem cells characterized by CD90 phenotype

Multiple uses of basement membrane‐like matrix (BME/Matrigel) in vitro and in vivo with cancer cells

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