Comparative Gene Expression Profiling of Primary and Metastatic Renal Cell Carcinoma Stem Cell-Like Cancer Cells

Khan, Mohammed I.; Czarnecka, Anna M.; Lewicki, Sławomir; Brodaczewska, Klaudia; Koch, Irena; Zdanowski, Robert; Król, Magdalena; Szczylik, Cezary

doi:10.1371/journal.pone.0165718

Cited by 33 publications

(28 citation statements)

References 102 publications

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“…In a metastatic RCC cell line, the expression of the OCT-4 and NANOG gene was significantly overexpressed compared to all other RCC cell lines (22). Our analysis also showed that higher levels of OCT-4 and NANOG expression were associated with worse survival of RCC patients, indicating these stem cell pluripotency factors might be a common pathway for inhibition of CSCs.…”

Section: Discussionsupporting

confidence: 55%

CBFA2T2 is Associated with a Cancer Stem Cell State in Renal Cell Carcinoma

Chen¹,

Liang²,

Wang³

et al. 2017

Preprint

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Renal cell carcinoma (RCC) is the most common kidney cancer, accounting for approximately 80-90 % of all primary kidney cancer. Treatment for patients with advanced RCC remains unsatisfactory. Rare cancer stem cells (CSCs) are proposed to be responsible for failure of current treatment. Here, we investigate the effects of CBFA2T2 on CSCs regulation in RCC, as well as to elucidate the possible mechanisms. We showed that CBFA2T2 expression can significantly predict the survival of RCC patients. Functional assays showed that knocking-down of CBFA2T2 can inhibit cell migration and invasion in 786-O and A-498 cells in vitro, and reduce ALDH high CSCs populations. Furthermore, CBFA2T2 expression is necessary for sphere-forming ability and cancer stem cells marker expression in RCC cell lines. Collectively, our data suggest that CBFA2T2 expression correlates with aggressive characteristics of RCC and CBFA2T2 is required for maintenance of "stemness" through regulation of stem cells factors, thereby highlighting CBFA2T2 as a potential therapeutic target for RCC treatment.KEYWORDS: CBFA2T2; renal cell carcinoma; cancer stem cells; OCT-4; NANOG INTRODUCTIONRenal cell carcinoma (RCC) represents one of the most common type of renal cancer, accounting for 90% of adult renal malignancies (1). The prognosis of advanced RCC is very poor, with a 5-year survival rate of 5-10% (2). In addition, around 20-40% of RCC patients developed recurrence after treatment (3). The mechanisms of how these metastasis and recurrence occur are largely uncharacterized. Recent studies have shown the presence of cancer stem cells (CSCs) in various solid tumor tissues (4-6). CSCs are undifferentiated multipotential tumor cells that have high tumorigenic activity and the capacity to self-renew (4, 5, 7). Moreover, CSCs promote cancer resistance to treatment and recurrence, leading to high mortality (5). Therefore, CSC-targeted therapy can be an essential part of cancer therapy.Previously, CSCs in RCC have been identified by using either stem cell markers (CD133, CD44, CXCR4 and CD105) (8-11) or functional assays (sphere-forming ability, side population and ALDH activity) (12)(13)(14). Especially, in RCC cell lines, ALDH high cells showed CSC properties in vitro, such as clonogenic and self-renewal ability and increased expression of OCT4 and NANOG (15). Importantly, in the metastatic RCC cell lines, ALDH high cells formed about 15% of the total number of cells and had higher Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted:

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Section: Discussionsupporting

confidence: 55%

CBFA2T2 is Associated with a Cancer Stem Cell State in Renal Cell Carcinoma

Chen¹,

Liang²,

Wang³

et al. 2017

Preprint

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“…High CD105 mRNA expression was previously associated with RCC metastases and high tumor stage 29 . In RCC cell lines CD105 www.nature.com/scientificreports www.nature.com/scientificreports/ was reported by us to be highly expressed in metastatic Caki-1 cell line before 12 , as well as by other groups 28 . Moreover, detection of CD105 marker in peripheral blood is considered to be effective tool to evaluate the early metastasis in RCC, especially in a cancer stem cell -positive conditions 30 .…”

Section: Discussionmentioning

confidence: 95%

“…Positive spheres were shown as green. present in most of RCC cell lines (SMKT-R3, Caki-2, 786-O, 769-P, RCC-6, Caki-1, ACHN and that CD105+ cells express also alkaline phosphatase (AP) 12 . The exact size of CD105+ cells subpopulation within the cell lines range from 0.03% (786-0), 0.06% (ACHN) to 2.17% (OS-RC2), but in as much as 90.93% (Caki-1) to 93.9% (SN12PM6) cells may be positive 28 .…”

Section: Discussionmentioning

confidence: 99%

“…CD105 was shown to play functional role in maintaining cancer stem cell phenotype and epithelial -mesenchymal transition (EMT) phenotype 31 , while cells after EMT disseminate to distant organs and form metastases 32 . Due to high expression of the CD105 marker, also in our previous study (4%) 12 Caki-1 cell line was used in the present study. As CD105−expressing subpopulation in human RCC xenografts from patient (nephrectomy) samples was shown to possess high capability of self-renewal and ability to form spheres in cell culture in vitro in complement to tumors in mice 28 it remains interesting that CD105− cells also give rise to tumors in our study.…”

Section: Discussionmentioning

confidence: 99%

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Renal carcinoma CD105−/CD44− cells display stem-like properties in vitro and form aggressive tumors in vivo

Fiedorowicz

Khan

Strzemecki

et al. 2020

Sci Rep

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clear cell renal cell carcinoma (ccRcc) is the most common kidney cancer. prognosis for ccRcc is generally poor since it is largely resistant to chemo-and radiotherapy. Many studies suggested that cancer stem cells/tumor initiating cells (CSCs/TICs) are responsible for development of tumor, disease progression, aggressiveness, metastasis and drug resistance. However, tumorigenic potential of CSCs/ tics isolated from established Rcc cell lines-basic ccRcc research model-has never been investigated in vivo. CD105+, CD105−, CD44+ and CD44− as well as CD44−/CD105− CD44+/CD105+ and CD44−/ CD105+ cells were isolated from Caki-1 RCC cell line, confirming coexistence of multiple subpopulations of stem-related phenotype in stable cell line. Sorted cells were injected subcutaneously into noD SciD mice and tumor growth was monitored with MRi and pet/ct. tumor growth was observed after implantation of CD105+, CD44+, CD44−, CD44−/CD105+ and CD44−/CD105− but not CD105− or CD44+/CD105+. Implantation of CD44−/CD105− cells induced tumors that were characterized by longer T1 and distinct metabolic pattern than other tumors. All the tumors were characterized by low uptake of [18F]FDG. CD105+ and CD44− tumors expresses Nanog and Oct-4, while CD44− tumors additionally expressed endothelial cell marker-CD31. Renal cell carcinoma (RCC), is the 10th malignancy worldwide and the most frequent type of kidney cancer in adults. Each year in Europe approximately 88 400 patients are diagnosed with RCC; the incidence and mortality of RCC are rising at a rate of 2-3% per decade, therefore novel therapies directed against RCC are needed. At the same time despite advancements in diagnostic techniques, up to 30% of newly diagnosed patients already present with metastases, and a large portion of patients that undergo surgical treatment experience the RCC recurrence, therefore drugs targeted against metastasis initiating cells would be of great interest in the future 1,2. Cancer stem cells (CSCs) are characterized by the potential to self-renew, high tumorigenicity in nude mice and the ability to efficiently reconstitute all tumor subpopulations and primary tumor phenotype 3-5. CSCs are also responsible not only for cancer development, but also for disease recurrence, progression and metastatic spread, together with cancer aggressiveness, including treatment resistance such as chemo/radiotherapy, and targeted treatment 6,7 , therefore basic research with careful model selection to understand their biology is mandatory to define novel potential therapeutic targets for all RCC subtypes 8,9 .

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“…Expression profiles were also compared on kidney cancer samples and lung metastases using Affymetrix microarrays to identify genes that could potentially be targets of therapy [61]. Gene expression profiles were studied using microarrays on cultured metastatic RCC (ACHN) and primary RCC (CAKI-2) cell lines, to identify and analyze cancer stem cells [62]. In the works presented here, as well as in the works devoted to the analysis of the expression of individual genes [4,[9][10][11], missing information on the applicability of the revealed differences in expression as markers of metastasis.…”

Section: Discussionmentioning

confidence: 99%

The Genes—Candidates for Prognostic Markers of Metastasis by Expression Level in Clear Cell Renal Cell Cancer

et al. 2020

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The molecular prognostic markers of metastasis are important for personalized approaches to clear cell renal cell carcinoma (ccRCC) treatment but markers for practical use are still missing. To address this gap we studied the expression of ten genes—CA9, NDUFA4L2, VWF, IGFBP3, BHLHE41, EGLN3, SAA1, CSF1R, C1QA, and FN1—through RT-PCR, in 56 ccRCC patients without metastases and with metastases. All of these, excluding CSF1R, showed differential and increased (besides SAA1) expression in non-metastasis tumors. The gene expression levels in metastasis tumors were decreased, besides CSF1R, FN1 (not changed), and SAA1 (increased). There were significant associations of the differentially expressed genes with ccRCC metastasis by ROC analysis and the Fisher exact test. The association of the NDUFA4L2, VWF, EGLN3, SAA1, and C1QA expression with ccRCC metastasis is shown for the first time. The CA9, NDUFA4L2, BHLHE4, and EGLN3 were distinguished as the strongest candidates for ccRCC metastasis biomarkers. We used an approach that presupposed that the metastasis marker was the expression levels of any three genes from the selected panel and received sensitivity (88%) and specificity (73%) levels with a relative risk of RR > 3. In conclusion, a panel of selected genes—the candidates in biomarkers of ccRCC metastasis—was created for the first time. The results might shed some light on the ccRCC metastasis processes.

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Comparative Gene Expression Profiling of Primary and Metastatic Renal Cell Carcinoma Stem Cell-Like Cancer Cells

Cited by 33 publications

References 102 publications

CBFA2T2 is Associated with a Cancer Stem Cell State in Renal Cell Carcinoma

CBFA2T2 is Associated with a Cancer Stem Cell State in Renal Cell Carcinoma

Renal carcinoma CD105−/CD44− cells display stem-like properties in vitro and form aggressive tumors in vivo

The Genes—Candidates for Prognostic Markers of Metastasis by Expression Level in Clear Cell Renal Cell Cancer

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