Cancer stem cells are underestimated by standard experimental methods in clear cell renal cell carcinoma

Gedye, Craig; Sirskyj, Danylo; Lobo, Nazleen; Meens, Jalna; Hyatt, Elzbieta; Robinette, Michael; Fleshner, Neil; Hamilton, Robert J.; Kulkarni, Girish S.; Zlotta, Alexandre R.; Evans, Andrew; Finelli, Antonio; Jewett, Michael A.S.; Ailles, Laurie

doi:10.1038/srep25220

Cited by 24 publications

(22 citation statements)

References 49 publications

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“…To observe tumor formation for both 8505c‐control and ‐silenced clones, we had to use a quite high cell number (10 7 ). Although the xenotransplantation method is the gold standard with which to define tumor‐initiating frequency, it has some limitations and can be influenced by multiple technical steps (i.e., mouse model, immune surveillance in the xenograft system, orthotopic implant and other factors) . Consequently, we cannot rule out that tumor‐initiating cell frequency was underestimated in our system.…”

Section: Discussionmentioning

confidence: 98%

Interleukin-8, but Not the Related Chemokine CXCL1, Sustains an Autocrine Circuit Necessary for the Properties and Functions of Thyroid Cancer Stem Cells

Liotti

Collina²,

Pone

et al. 2016

Stem Cells

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Interleukin-8 (IL-8/CXCL8) mediates its biological effects through two receptors, CXCR1 and CXCR2. While CXCR1 recognizes IL-8 and granulocyte chemotactic protein-2, CXCR2 binds to multiple chemokines including IL-8, CXCL1, 2 and 3. Both IL-8 and CXCL1 have been implicated in the neoplastic features of thyroid cancer (TC). Here, we assessed the role of the autocrine circuits sustained by IL-8 and CXCL1 in determining TC stem cell (TC SC) features. Using immunohistochemistry, we found that thyroid epithelial cancerous, but not normal, cells stained positive for IL-8, whose levels correlated with lymph-nodal metastases. We assessed the expression of endogenous IL-8 and CXCL1, by ELISA assays, and of their receptors CXCR1 and CXCR2, by flow cytometry, in a panel of TC cell lines. These molecules were expressed in TC cell lines grown in adherence, and at higher levels also in thyrospheres enriched in stem-like cells. RNA interference demonstrated that IL-8/CXCR1, but not CXCL1/CXCR2, is crucial for the sphereforming, self-renewal and tumor-initiating ability of TC cells. Accordingly, treatment of TC cells with IL-8, but not with CXCL1, potentiated cell stemness. We identified CD34 as an IL-8-induced gene and as a TC SC marker, since it was overexpressed in thyrospheres compared to adherent cells. Moreover, CD34 is required for the efficient sphere-forming ability and tumorigenicity of TC cells. Our data indicate that IL-8, but not the CXCL1 circuit, is critical for the regulation of TC SCs, and unveils novel potential targets for the therapy of as yet untreatable forms of TC. STEM CELLS 2017;35:135-146 SIGNIFICANCE STATEMENTThyroid cancer (TC) contains a subpopulation of stem-like cells endowed with cancer-initiating ability and intrinsic resistance to conventional therapeutics. Aggressive and undifferentiated forms of TC contain a higher percentage of TC stem cells (TC SCs). These tumors generally do not respond to conventional therapies. An alternative therapeutic approach might be the selective targeting of TC SCs. Here, we provide evidence that an autocrine circuit involving IL-8 is critical in the sphere formation, self-renewal and tumor-initiating ability of TC SCs. Targeting the IL-8/CXCR1 circuit could be a novel therapeutic strategy for patients with untreatable TC.

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Section: Discussionmentioning

confidence: 98%

Interleukin-8, but Not the Related Chemokine CXCL1, Sustains an Autocrine Circuit Necessary for the Properties and Functions of Thyroid Cancer Stem Cells

Liotti

Collina²,

Pone

et al. 2016

Stem Cells

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“…This theory has been studied further in acute myeloid leukemia, breast cancer and other cancer types (27,28). CSCs in RCC have also been studied (29,30). It has been reported that the expression of Bmi-1, a gene that may promote self-renewal of stem cells and whose mutation may lead to tumor initiation, is inversely proportional to the degree of RCC differentiation (31).…”

Section: Discussionmentioning

confidence: 99%

Significance of cyclooxygenase‑2, prostaglandin E2 and CD133 levels in sunitinib‑resistant renal cell carcinoma

et al. 2019

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The current study investigated the mechanism underlying sunitinib resistance. The parental human renal cell carcinoma (RCC) cell line 786-O was continuously exposed to various doses of sunitinib to obtain sunitinib-resistant cells (786-O/S). Cell proliferation and colony formation assays were performed to assess the survival of 786-O/S cells. The half-inhibitory concentration for the drug-resistant cells was calculated. 786-O/S cells demonstrated notably morphological changes compared with parental cells. Compared with 786-O cells, 786-O/S cells exhibited stronger proliferative and colony-forming abilities. Western blot analysis was performed to measure the levels of cyclooxygenase 2 (COX-2) and prostaglandin E2 (PGE2). Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was used to detect the expression of COX-2 and cluster of differentiation (CD) 133 in both 786-O and 786-O/S cells. Following incubation of the two cell lines with celecoxib, a COX-2 inhibitor, RT-qPCR was performed to detect the expression of COX-2 and CD133, and western blot analysis was used to assess the expression of CD133. The results revealed that the levels of COX-2 and PGE2 were significantly higher in 786-O/S cells compared with 786-O cells (P<0.01). Similarly, the expression of CD133 was 24-fold higher in 786-O/S compared with the parental cells (P<0.01). When celecoxib was incubated with the two cell lines, the expression of COX-2 and CD133 decreased significantly (P<0.0001). In summary, the results indicate that activation of the COX-2-PGE2 pathway in RCC leads to the development of sunitinib resistance and may serve an important role in the maintenance of the characteristics of stem cells that are closely associated with drug resistance.

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“…S5A). In vitro serial limited dilution assay showed that receptor knock down in OVCAR5 cells caused a decreased stem cells frequency, as calculated by the ELDA software (28) To test the effects of FZD7 on tumor formation, a subcutaneous (s.c.) xenograft model was used.…”

Section: Frizzled 7 (Fzd7) Is Upregulated In Platinum Tolerant Oc Celmentioning

confidence: 99%

Frizzled-7 Identifies Platinum Tolerant Ovarian Cancer Cells Susceptible to Ferroptosis

Wang

Zhao

Condello

et al. 2020

Preprint

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The authors have no conflicts of interest to declare. AbstractDefining traits of platinum tolerant cancer cells could expose new treatment vulnerabilities. Here, new markers associated with platinum tolerant cells and tumors were identified by using in vitro and in vivo ovarian cancer (OC) models treated repetitively with carboplatin and validated in human specimens. Platinum-tolerant cells and tumors were found to be enriched in ALDH (+) cells, formed more spheroids, and expressed increased levels of stemness-related transcription factors compared to parental cells. Additionally, platinum-tolerant cells and tumors highly expressed the Wnt receptor, Frizzled 7 (FZD7). FZD7 knock down improved sensitivity to platinum, decreased spheroid formation, and delayed tumor initiation. The molecular signature distinguishing FZD7(+) from FZD7(-) cells included epithelial-to-mesenchymal (EMT), stemness, and oxidative phosphorylation enriched gene sets. Overexpression of FZD7 activated the oncogenic factor Tp63, driving upregulation of glutathione metabolism pathways, including glutathione peroxidase 4 (GPX4), which protects cells from chemotherapy-induced oxidative stress. FZD7(+) platinum-tolerant OC cells were more sensitive and underwent ferroptosis after treatment with GPX4 inhibitors. FZD7, Tp63 and glutathione metabolism gene sets were strongly correlated in the OC Tumor Cancer Genome Atlas (TCGA) database and in human OC specimens residual after chemotherapy. These results support the existence of a platinum-tolerant cell population with partial stem cell features, characterized by FZD7 expression and dependent on FZD7-b-catenin-Tp63-GPX4 pathway for survival. The findings reveal a novel therapeutic vulnerability of platinum tolerant cancer cells and provide new insight into a potential "persister cancer cell" phenotype.glutathione peroxidase 4 (GPX4) tumor initiation capacity (TIC) (10). Importantly, ovarian CSCs possess a phenotype associated with drug resistance, including enhanced DNA repair, diminished apoptotic responses, increased efflux mechanisms and enhanced antioxidation defense (8,11), which allow them to escape from chemotherapy. The boundaries between stemness and chemotherapy tolerant phenotypes remain blurry and while an overlap exists, it is assumed that distinct pathways drive the two entities.As platinum tolerant cancer cells drive tumor relapse, decreasing survival rate of women with OC, we aimed to identify specific markers, by using in vitro and in vivo models of repeated exposure to the cytotoxic agent. We observed that platinum-tolerant cells and tumors contained an increased ALDH+ cell population, expressing stemness related transcription factors (TFs), and able to form more spheroids compared to chemotherapy naïve cells. We identified the Frizzled 7 receptor (FZD7) as a novel cell surface marker significantly upregulated in the platinum tolerant cell population. FZD7 knock down increased sensitivity to platinum, decreased spheroid formation in vitro, and delayed tumor initiation in vivo. FZD7...

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Cancer stem cells are underestimated by standard experimental methods in clear cell renal cell carcinoma

Cited by 24 publications

References 49 publications

Interleukin-8, but Not the Related Chemokine CXCL1, Sustains an Autocrine Circuit Necessary for the Properties and Functions of Thyroid Cancer Stem Cells

Interleukin-8, but Not the Related Chemokine CXCL1, Sustains an Autocrine Circuit Necessary for the Properties and Functions of Thyroid Cancer Stem Cells

Significance of cyclooxygenase‑2, prostaglandin E2 and CD133 levels in sunitinib‑resistant renal cell carcinoma

Frizzled-7 Identifies Platinum Tolerant Ovarian Cancer Cells Susceptible to Ferroptosis

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