Cancer Stem Cell Gene Profile as Predictor of Relapse in High Risk Stage II and Stage III, Radically Resected Colon Cancer Patients

Scartozzi, Mario; Loretelli, Cristian; Piva, Francesco; Mandolesi, Alessandra; Lezoche, Giovanni; Prete, Michela Del; Bittoni, Alessandro; Faloppi, Luca; Bianconi, Maristella; Cecchini, Luca; Guerrieri, Mario; Bearzi, Italo; Cascinu, Stefano

doi:10.1371/journal.pone.0072843

Cited by 37 publications

(37 citation statements)

References 28 publications

(25 reference statements)

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“…The development of multiple drug resistance (MDR) in tumors is considered to be the major obstacle in the treatment of CRC. Certain members of the ATP-binding cassette (ABC) family of transporters facilitate drug resistance in numerous types of cancer, and recent clinical data correlates the expression of ABC transporters to the risk of relapse in CRC patients (3).…”

Section: Introductionmentioning

confidence: 99%

“…MDR transporters within this superfamily include P-glycoprotein (P-gp) and the breast cancer resistance protein ABC subfamily G member 2 (ABCG2) (8). P-gp and ABCG2 play major roles in the ATP-dependent export of chemotherapeutic drugs and contribute to the MDR phenotype observed in CRC, although the expression of these transporters may vary depending on the stage of the disease (3,9). For patients with advanced-stage CRC, ABCG2 is a promising therapeutic target and the focus of recent efforts to identify pharmacophores that effectively inhibit its efflux function (10).…”

Section: Introductionmentioning

confidence: 99%

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Hedyotis diffusa Willd overcomes 5-fluorouracil resistance in human colorectal cancer HCT-8/5-FU cells by downregulating the expression of P-glycoprotein and ATP-binding casette subfamily G member 2

Wang

Shen

et al. 2015

Experimental and Therapeutic Medicine

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Abstract. Previous studies have demonstrated thatHedyotis diffusa Willd (HDW), a traditional Chinese herbal medicine, exhibits potent anticancer activity in models of colorectal cancer (CRC). Aggressive forms of CRC exhibit resistance to widely used chemotherapeutic drugs, including the antimetabolite, 5-fluorouracil (5-FU); however, less is known with regard to the activity of HDW against 5-FU-resistant cancer. In the present study, the mechanism of action and the potency of ethanol extracts of HDW (EEHDW) were investigated on a multidrug-resistant CRC HCT-8/5-FU cell line. Using an MTT cell proliferation assay, EEHDW treatment was shown to significantly reduce the cell viability of HCT-8/5-FU cells in a dose-and time-dependent manner. Furthermore, EEHDW significantly increased the retention of the ATP-binding cassette (ABC) transporter substrate, rhodamine-123, as compared with the untreated controls. To further investigate the molecular mechanisms targeted by EEHDW in the resistant cells, the expression levels of the ABC drug transporter protein, P-glycoprotein (P-gp), and ABC subfamily G member 2 (ABCG2), were analyzed using reverse-transcription polymerase chain reaction and western blot analysis. The mRNA and protein expression levels of P-gp and ABCG2 were reduced in the HCT-8/5-FU cells following EEHDW treatment, indicating that EEHDW inhibits ABCG2-mediated drug resistance by downregulating the expression of ABCG2 and P-gp. Therefore, the potential application of EEHDW as a chemotherapeutic adjuvant represents a promising alternative approach to the treatment of drug-resistant CRC.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Hedyotis diffusa Willd overcomes 5-fluorouracil resistance in human colorectal cancer HCT-8/5-FU cells by downregulating the expression of P-glycoprotein and ATP-binding casette subfamily G member 2

Wang

Shen

et al. 2015

Experimental and Therapeutic Medicine

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“…ZP3 is expressed mostly in oocytes and sperm and relevance of its mutation in liver metastasis is unknown 32, 50 . Mutated DTX2 is a negative regulator of Notch signaling and lower DTX2 expression in colon cancer patients is associated with unfavorable outcome 19, 26 . Although non-synonymous mutations involving Notch pathway were not seen with breast cancer liver metastasis, inversion of NOTCH2 gene was observed (Fig 2D).…”

Section: Resultsmentioning

confidence: 99%

A system for detecting high impact-low frequency mutations in primary tumors and metastases

et al. 2017

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Tumor complexity and intratumor heterogeneity contribute to subclonal diversity. Despite advances in next-generation sequencing (NGS) and bioinformatics, detecting rare mutations in primary tumors and metastases contributing to subclonal diversity is a challenge for precision genomics. Here, in order to identify rare mutations, we adapted a recently described epithelial reprograming assay for short-term propagation of epithelial cells from primary and metastatic tumors. Using this approach, we expanded minor clones and obtained epithelial cell-specific DNA/RNA for quantitative NGS analysis. Comparative Ampliseq Comprehensive Cancer Panel sequence analyses were performed on DNA from unprocessed breast tumor and tumor cells propagated from the same tumor. We identified previously uncharacterized mutations present only in the cultured tumor cells, a subset of which has been reported in brain metastatic but not primary breast tumors. In addition, whole-genome sequencing identified mutations enriched in liver metastases of various cancers, including Notch pathway mutations/chromosomal inversions in 5/5 liver metastases, irrespective of cancer types. Mutations/rearrangements in FHIT, involved in purine metabolism, were detected in 4/5 liver metastases, and the same four liver metastases shared mutations in 32 genes, including mutations of different HLA-DR family members affecting OX40 signaling pathway, which could impact the immune response to metastatic cells. Pathway analyses of all mutated genes in liver metastases showed aberrant tumor necrosis factor and transforming growth factor signaling in metastatic cells. Epigenetic regulators including KMT2C/MLL3 and ARID1B, which are mutated in >50% of hepatocellular carcinomas, were also mutated in liver metastases. Thus, irrespective of cancer types, organ-specific metastases may share common genomic aberrations. Since recent studies show independent evolution of primary tumors and metastases and in most cases mutation burden is higher in metastases than primary tumors, the method described here may allow early detection of subclonal somatic alterations associated with metastatic progression and potentially identify therapeutically actionable, metastasis-specific genomic aberrations.

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“…Besides introduced markers listed in Table 1 Apart from in vitro studies, analyzing clinical samples revealed that CD44 could be used in combination with clinicopathological information to improve the OSCC prognosis, since its overexpression, in tumor samples and peripheral blood of OSCC patients, was correlated to poor prognosis LGR5 [152,153] EpCAM [120] BMI1 [119,218] CD24 [122,125] OCT4 [118,119] SOX2 [118,119,[149][150][151] NANOG [118,119] Colon and rectum CD44 [166,[180][181][182][183][184][185][186][187][188][189][190][191][192][193][194][195][196][197][198]200] CD133 [161-165, 171-178, 186-188, 232] ABCG2 [75,158,159] ALDH1 [198,[222][223][224]…”

Section: Oral Cavitymentioning

confidence: 99%

“…In addition, CD44v9, associated with tumorigenicity and drug resistance of CRC-SCs [194], was proposed as a useful marker for predicting recurrence, prognosis, and treatment efficacy [195]. However, CD44 has not been widely accepted as a clinical marker for CRC-SCs, since a number of studies indicated an association between its expression and rate of survival and tumor relapse [180,[196][197][198], while others reported no correlation [178,179].…”

Section: Colon and Rectummentioning

confidence: 99%

Cancer stem cells in human digestive tract malignancies

2015

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Digestive tract malignancies, including oral, pharyngeal, esophageal, gastric, and colorectal cancers, are among the top 10 most common cancers worldwide. In spite of using various treatment modalities, cancer patients still suffer from recurrence and metastasis of malignant cells. Cancer stem cells (CSCs) are undifferentiated and highly proliferative malignant cells with unique properties mediated by overexpression of stemness markers, metastasis-related proteins, drug transporters, and DNA repair machinery. Due to their salient characteristics, it has been suggested that CSCs are responsible for tumor initiation, progression, invasion, recurrence, and therapy resistance. Exploring different aspects of CSC biology has fueled a great enthusiasm in designing novel therapeutic strategies to help patients. For instance, identification of markers associated with digestive tract CSCs, such as CD44, CD133, CD24, EpCAM, LGR5, ALDH1, and BMI1, has made it possible to develop more accurate diagnosis approaches. In addition, specifically targeting CSCs by their markers imposes fewer side effects and improves therapeutic outcomes. Here, we focus on the current status of CSC biology in digestive tract cancers, with emphasis on CSC markers, and review achieved progress in eradication of digestive tract CSC cells.

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Cancer Stem Cell Gene Profile as Predictor of Relapse in High Risk Stage II and Stage III, Radically Resected Colon Cancer Patients

Cited by 37 publications

References 28 publications

Hedyotis diffusa Willd overcomes 5-fluorouracil resistance in human colorectal cancer HCT-8/5-FU cells by downregulating the expression of P-glycoprotein and ATP-binding casette subfamily G member 2

Hedyotis diffusa Willd overcomes 5-fluorouracil resistance in human colorectal cancer HCT-8/5-FU cells by downregulating the expression of P-glycoprotein and ATP-binding casette subfamily G member 2

A system for detecting high impact-low frequency mutations in primary tumors and metastases

Cancer stem cells in human digestive tract malignancies

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