Detecting and targeting mesenchymal-like subpopulations within squamous cell carcinomas

Basu, Devraj; Montone, Kathleen T.; Wang, Liping; Gimotty, Phyllis A.; Hammond, Rachel; Diehl, J. Alan; Rustgi, Anil K.; Lee, John Tayu; Räsänen, Kati; Weinstein, Gregory S.; Herlyn, Meenhard

doi:10.4161/cc.10.12.15883

Cited by 40 publications

(45 citation statements)

References 26 publications

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“…Cell Lines and Cell Culture-OCTT2 cell line, derived from a human HNSCC primary surgical specimen, and FEF3 primary fibroblast strain, isolated from human fetal esophagus and stably transduced with green fluorescent protein, have been described previously and were cultured as detailed earlier (3,4,16). For preparation of conditioned medium (CM), cells were cultured overnight in serum-free conditions after which supernatant was collected, centrifuged, and filtered through low protein binding filters (EMD Millipore Corporation, Billerica, MA) to remove cell debris.…”

Section: Methodsmentioning

confidence: 99%

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Comparative Secretome Analysis of Epithelial and Mesenchymal Subpopulations of Head and Neck Squamous Cell Carcinoma Identifies S100A4 as a Potential Therapeutic Target

Räsänen

Sriswasdi

Valiga

et al. 2013

Molecular & Cellular Proteomics

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Epithelial-mesenchymal transition (EMT) is a key contributor in tumor progression and metastasis. EMT produces cellular heterogeneity within head and neck squamous cell carcinomas (HNSCC) by creating a phenotypically distinct mesenchymal subpopulation that is resistant to conventional therapies. In this study, we systematically characterized differences in the secretomes of E-cadherin high epithelial-like and E-cadherin low mesenchymal-like subpopulations using unbiased and targeted proteomics. A total 1765 proteins showed significant changes with 177 elevated in the epithelial subpopulation and 173 elevated in the mesenchymal cells. Key nodes in affected networks included NF B, Akt, and ERK, and most implicated cellular components involved various aspects of the extracellular matrix. In particular, large changes were observed in multiple collagens with most affected collagens at much higher abundance levels in the mesenchymal subpopulation. These cells also exhibited a secretome profile resembling that of cancer-associated fibroblastic cells (CAF). S100A4, a commonly used marker for cancer-associated fibroblastic cells, was elevated more than 20-fold in the mesenchymal cells and this increase was further verified at the transcriptome level. S100A4 is a known mediator of EMT, leading to metastasis and EMT has been proposed as a potential source of cancer-associated fibroblastic cells in solid tumors. S100A4 knockdown by small interfering RNA led to decreased expression, secretion and activity of matrix metalloproteinase 2, as verified by quantitative PCR, multiple reaction monitoring and zymography analyses, and reduced invasion in collagen-embedded spheroids. Further confirmation in three-dimensional organotypic reconstructs showed less invasion and advanced differentiation in the S100A4 RNA interference samples. Head and neck squamous cell carcinoma (HNSCC) 1 is the sixth most common cancer worldwide with high morbidity and mortality. Treatment options are limited; surgery, radiation and conventional chemotherapy are generally associated with considerable impairment to quality of life (1). Currently cetuximab, the anti-epidermal growth factor receptor (EGFR) monoclonal antibody, is the only FDA-approved molecularly targeted drug for HNSCC. Several clinical trials are underway that target EGFR or other tyrosine kinases, but many have failed to progress beyond Phase II (2). One reason behind the failure of new treatment options for HNSCC is resistance to therapy, which tumor heterogeneity is thought to provide.

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Section: Methodsmentioning

confidence: 99%

“…We have previously shown that an E-cadherin low mesenchymal subpopulation (MSP) within a predominantly epithelial carcinoma confers resistance to both conventional chemotherapy and cetuximab treatment (3,4). Epithelial and mesenchymal subpopulations within these tumors exhibited phenotypic plasticity, indicative of epithelial-mesenchymal transition (EMT) (3).…”

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confidence: 99%

Comparative Secretome Analysis of Epithelial and Mesenchymal Subpopulations of Head and Neck Squamous Cell Carcinoma Identifies S100A4 as a Potential Therapeutic Target

Räsänen

Sriswasdi

Valiga

et al. 2013

Molecular & Cellular Proteomics

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“…It has recently been reported that salinomycin can selectively kill human breast cancer stem cells, and is 100-fold more effective at reducing the proportion of CSCs than paclitaxel, albeit by an unknown mechanism (19). Salinomycin was also found to be a selective inhibitor of human lung, gastric, osteosarcoma, squamous cell carcinoma, prostate and pancreatic CSCs (20)(21)(22)(23)(24)(25). However, since the mechanism involved in the salinomycin anti-CSC activity is poorly understood, it is necessary to conduct more in-depth research into the activity of salinomycin in different types of human CSCs.…”

Section: Introductionmentioning

confidence: 99%

Salinomycin inhibits the growth of colorectal carcinoma by targeting tumor stem cells

Zhang

Tian

Song³

et al. 2015

Oncology Reports

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Abstract. Salinomycin is a monocarboxylic polyether antibiotic that has been reported to induce apoptosis in various types of cancer cells with specificity for cancer stem cells. However, its anticancer effect in colorectal cancer stem cells has never been reported. In the present study, we examined the ability of salinomycin to induce cell death in the colorectal cancer stem cell line CD44 + EpCAM + HCT-116, and we measured its in vivo tumor inhibition capacity. Salinomycin dose-dependently induced cytotoxicity in the CD44 + EpCAM + HCT-116 cells and inhibited colony formation. Salinomycin treatment was shown to induce apoptosis, as evidenced by nuclear fragmentation, an increase in the proportion of acridine orange/ethidium bromide-positive cells and an increase in the percentage of Annexin V-positive cells. Apoptosis was induced in colorectal cancer stem cells in a caspase-dependent manner, as shown by an increase in the levels of cleaved caspase-3, -8 and -9. JC-1 staining further revealed that salinomycin induced colorectal cancer cell apoptosis via the mitochondrial pathway. In addition, salinomycin treatment of xenograft mice inhibited the growth of tumors derived from the CD44 + EpCAM + HCT-116 cells. The present study demonstrated that the antibiotic salinomycin exerts an anti-colorectal cancer effect in vitro and in vivo, suggesting salinomycin as a potential drug for colorectal cancer therapy. IntroductionColorectal cancer (CRC) is the third most common malignancy worldwide, accounting for ~10% of all cancer cases and CRC is one of the most common causes of death related to gastrointestinal cancers (1-3). Although the incidence rates of colon cancer have declined somewhat, current therapies are associated with serious side-effects, high cost and recurrence rates exceeding 50%, primarily due to the development of acquired chemoresistance to conventional chemotherapeutics (4,5).Emerging data suggest that malignant tumors contain a small distinct population of cancer stem cells (CSCs), which are responsible for tumor initiation and propagation (6). Stem cell research and the cancer stem cell (CSC) hypothesis have shown that colonic stem cells or CSCs are involved in tissue regeneration and colonic carcinogenesis (7-9). Drug-resistant CSCs are thought to be one of the key causes of CRC treatment failure, and it is hypothesized that these cells are ultimately the likely cause of metastasis and tumor recurrence (10-12). Most modern treatments are ineffective against solid tumors and this may be the result of the increased resistance of CSCs (13). Therefore, it is vital to find novel therapeutic methods to eradicate CSCs and enable the development of more effective treatment protocols (14).Salinomycin is a 751-Da monocarboxylic polyether antibiotic, which was initially used to eliminate bacteria, fungi and parasites and is fed to ruminants to improve nutrient absorption and feeding efficiency (15,16). This compound is now considered an important anticancer drug candidate (17,18). It has recently been reporte...

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“…CSCs (Basu et al, 2011;Dong et al, 2011;Fuchs et al, 2010;Gupta et al, 2009;Ketola et al, 2012;Wang, 2011;Zhang et al, 2011b;Zhi et al, 2011). Additionally, inhibition of the Notch signaling pathway in glioblastoma and colon CSCs has been shown to promote terminal differentiation (Fan et al, 2010;Sikandar et al, 2010) antagonists, has also been effective in sensitizing AML to cytarabine, a key pyrimidine antimetabolite used in AML treatment (Kobune et al, 2009).…”

mentioning

confidence: 96%

The bad seed: Cancer stem cells in tumor development and resistance

Koren

Fuchs

2016

Drug Resistance Updates

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Detecting and targeting mesenchymal-like subpopulations within squamous cell carcinomas

Cited by 40 publications

References 26 publications

Comparative Secretome Analysis of Epithelial and Mesenchymal Subpopulations of Head and Neck Squamous Cell Carcinoma Identifies S100A4 as a Potential Therapeutic Target

Comparative Secretome Analysis of Epithelial and Mesenchymal Subpopulations of Head and Neck Squamous Cell Carcinoma Identifies S100A4 as a Potential Therapeutic Target

Salinomycin inhibits the growth of colorectal carcinoma by targeting tumor stem cells

The bad seed: Cancer stem cells in tumor development and resistance

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