The role of cancer stem cells in tumor heterogeneity and resistance to therapy

Konrad, Christina Valbirk; Murali, Reshma; Varghese, Binitha Anu; Nair, Radhika

doi:10.1139/cjpp-2016-0079

Cited by 39 publications

(34 citation statements)

References 180 publications

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“…Cancer stem cells (CSCs) are assumed to be a group of cells with the ability to initiate tumour growth, self-renew and differentiate and are implicated in tumour initiation, progression, metastasis, recurrence and resistance to therapy. [13][14][15][16] Researchers have now provided evidence of the existence of CSCs that were isolated from several types of human tumours, such as brain tumours, breast cancer and colon cancer. [17][18][19] It has been previously shown that stem cells cultured in suspension could generate nonadherent spherical clusters of cells composed of stem cells and progenitor cells.…”

Section: Discussionmentioning

confidence: 99%

Carboxypeptidase A4 promotes proliferation and stem cell characteristics of hepatocellular carcinoma

Zhang

Wang

Shang

et al. 2019

Int J Experimental Path

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Summary Carboxypeptidase A4 (CPA4), a member of the metallo‐carboxypeptidase family, is overexpressed in liver cancer and is associated with cancer progression. The role of CPA4 in hepatocellular carcinoma (HCC) remains unclear. In this study, we aimed to evaluate the relevance of CPA4 to the proliferation and expression of stem cell characteristics of hepatocellular carcinoma cells. Western blot analysis showed high CPA4 expression in the liver cancer cell line Bel7402 and low expression in HepG2 cells. Knock‐down of CPA4 decreased cancer cell proliferation as detected by MTT and clone formation assays. The serum‐free culture system revealed that downregulated CPA4 suppressed the sphere formation capacities of tumour cells. However, upregulated CPA4 increased the proliferation and sphere formation capacity. In addition, the protein expression of CD133, ALDH1 and CD44 also increased in cells with upregulated CPA4. In vivo, the overexpression of CPA4 in tumour cells that were subcutaneously injected into nude mice markedly increased the growth of the tumours. These data suggest that CPA4 expression leads to poor prognoses by regulating tumour proliferation and the expression of stem cell characteristics and may therefore serve as a potential therapeutic target of HCC.

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Section: Discussionmentioning

confidence: 99%

Carboxypeptidase A4 promotes proliferation and stem cell characteristics of hepatocellular carcinoma

Zhang

Wang

Shang

et al. 2019

Int J Experimental Path

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“…Therefore, the CSCs concept can provide effective intervention strategies to prevent and treat cancers. In recent years, increasing evidence have supported the theory that chemo‐resistance arises from CSCs, which can shield cancers from chemotherapeutic agents . Understanding the mechanisms underlying the acquisition of CSC population can hold the key to therapy resistance.…”

Section: Discussionmentioning

confidence: 99%

EGCG inhibits CSC‐like properties through targeting miR‐485/CD44 axis in A549‐cisplatin resistant cells

Jiang

Chen

et al. 2018

Molecular Carcinogenesis

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Non-small cell lung cancer (NSCLC) remains one of the most aggressive tumors with low life expectancy worldwide. The existence of cancer stem cells (CSCs) contributes to the failure of cancer treatment resulted from drug resistance. Altered microRNA expression has been observed in human tumors due to its role in tumor growth, progression, and metastasis. Hence, the aim of our present study was to investigate the effects of miR-485 on the CSC-like traits in NSCLC A549-cisplatin resistant cells and concentrate on the underlying molecular mechanism. It was found that CSC-like phenotypes were much more enriched in A549/cisplatin (A549/CDDP) cells compared to A549-parental cells. In addition, we observed that miR-485 was greatly decreased in A549/CDDP cells and miR-485 overexpression was able to decrease the stemness of A549/DDP cells. Meanwhile, epigallocatechin-3-gallate (EGCG), a green tea polyphenol which has been identified as an effective anticancer compound was able to increase miR-485 expression dose-dependently in A549/CDDP cells. Inhibitors of miR-485 remarkably increased CSC-like phenotypes, which could be reversed by indicated doses of EGCG. Moreover, CD44 was predicted as downstream target of miR-485 and the correlation between them was validated by performing dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assay. Subsequently, in vivo experiments were employed to confirm that EGCG restrained CSC-like characteristics by increasing miR-485 and decreasing CD44 expression. Taken together, it was implied that stemness features and CSC population were suppressed by EGCG-modulated miR-485/CD44 axis in A549/CDDP cells.

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“…It is largely documented that tumor initiating stem cells, along with being resistant to standard anticancer drugs are also able to promote progression of cancer and this progression is the result of increase in their self-renewal potential which is caused by drug-induced compensation (5, 31, 32). This highlights the need for effective therapeutic interventions targeting these CSCs.…”

Section: Discussionmentioning

confidence: 99%

“…Similar to many other cancers, PrCr is also caused by a small population of malignant stem cells known as cancer stem cells (CSCs) or tumor-initiating cells (TICs), which are responsible for tumor development, metastasis, and resistance to anti-cancer therapies (4). Numerous studies on many cancer types have demonstrated that the tumorigenic cells expressing common CSC markers, in particular CD133 and CD44, are resistant to conventional anti-cancer drugs and these cells can propagate significantly after therapy (5). The mechanisms of drug resistance in CSCs are thought to be dependent on several factors including up-regulated expression of drug efflux transporters, the activation of anti-apoptotic signaling pathways, inactivation of apoptotic machinery, a state of quiescence, an enhanced DNA damage response and active repair mechanisms.…”

Section: Introductionmentioning

confidence: 99%

Nanoemulsion formulation of a novel taxoid DHA-SBT-1214 inhibits prostate cancer stem cell-induced tumor growth

et al. 2017

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The main aim of this study was to evaluate the therapeutic efficacy of an oil-in-water nanoemulsion formulation encapsulating DHA-SBT-1214, a novel omega-3 fatty acid conjugated taxoid prodrug, against prostate cancer stem cells. Nanoemulsions of DHA-SBT-1214 (NE-DHA-SBT-1214) were prepared and characterized. In vitro delivery efficiency and cytotoxicity of NE-DHA-SBT-1214 was compared with solution formulation in PPT2 cells. In vivo studies included analysis of comparative efficacy of NE-DHA-SBT-1214 with Abraxane® and placebo nanoemulsions as well as post-treatment alternations in clonogenic and sphere-forming capabilities of the tumor cells. Qualitative intracellular uptake studies of dye encapsulated NEs by confocal imaging showed uptake by both monolayer and spheroid cultured PPT2 cells. Treatment of PPT2 cells with NE DHA-SBT-1214 (1nM-1μM for monolayer culture of cells grown on collagen-coated dishes for 48 hrs.) induced complete cell death, showing higher efficacy as compared to the drug solution. This nanoemulsion (10nM-10μM) also showed toxicity in 3D culture of floating spheroids. Weekly intravenous administration of the NE-DHA-SBT-1214 to NOD/SCID mice bearing subcutaneous PPT2 tumor xenografts led to dramatic suppression of tumor growth compared to Abraxane® and placebo nanoemulsion formulation. Viable cells that survived from this in vivo treatment regimen were no longer able to induce floating spheroids and holoclones, whereas control and Abraxane® treated tumor cells induced a large number of both. The results show that NE-DHA-SBT-1214 possesses significant activity against prostate CD133high/CD44+/high tumor-initiating cells both in vitro and in vivo.

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The role of cancer stem cells in tumor heterogeneity and resistance to therapy

Abstract: https://mc06.manuscriptcentral.com/cjpp-pubs Cancer is a heterogenous disease displaying marked inter-and intra-tumoral diversity. The

Cited by 39 publications

References 180 publications

Carboxypeptidase A4 promotes proliferation and stem cell characteristics of hepatocellular carcinoma

Carboxypeptidase A4 promotes proliferation and stem cell characteristics of hepatocellular carcinoma

EGCG inhibits CSC‐like properties through targeting miR‐485/CD44 axis in A549‐cisplatin resistant cells

Nanoemulsion formulation of a novel taxoid DHA-SBT-1214 inhibits prostate cancer stem cell-induced tumor growth

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