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Altered characteristics of cancer stem/initiating cells in a breast cancer cell line treated with persistent 5-FU chemotherapy.

ABSTRACT: Drug resistance of cancer stem/initiating cells has been considered to be one of the main reasons for tumor relapse. However, knowledge concerning the changes in stem/ initiating cells during chemotherapy is limited. In the present study, the breast cancer cell line MDA-MB-468 was cultured with 5-fluorouracil and serially passaged. Six cell generations were collected. Semi-quantitative RT-PCR and flow cytometric techniques were used to evaluate the protein and mRNA expression of stem/initiating factors (CD44(+)/CD24(-), Oct 3/4, SOX2 and ?-catenin), drug-resistance genes (BCRP and MRP1) and an anti-apoptosis gene (survivin). The clone formation rate was also examined in every generation of cells. The results showed that, under conditions of persistent chemotherapy, the factors representing the quantity of stem/initiating cells (?-catenin, Oct 3/4 and SOX2) followed a fluctuating trend of decrease-increase-further increase-decrease-increase-decrease, and factors representing the proportion of stem/initiating cells (proportion of CD44(+)/CD24(-) and the clone formation rate) demonstrated a fluctuating trend of increase-further increase-further increase-decrease. The drug-resistance genes (BCRP and MRP1) and the anti-apoptosis gene (survivin) demonstrated a wave of increase-further increase-further increase-decrease-increase (MRP1 decrease)-decrease. ?-catenin, Oct 3/4 and SOX2 showed a positive correlation (r=1, p<0.01). Our study confirmed that the drug resistance of cancer cells is mainly due to tumor stem/initiating cells, and that under conditions of persistent chemotherapy, the quantity or function of breast cancer stem/initiating cells increases and decreases alternately.

SUBMITTER: Lu X

PROVIDER: S-EPMC3440734 | biostudies-literature | 2011 Sep

REPOSITORIES: biostudies-literature

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Altered characteristics of cancer stem/initiating cells in a breast cancer cell line treated with persistent 5-FU chemotherapy.

Lü Xinquan X Deng Qing Q Li Huixiang H Suo Zhenhe Z

Experimental and therapeutic medicine 20110602 5

Drug resistance of cancer stem/initiating cells has been considered to be one of the main reasons for tumor relapse. However, knowledge concerning the changes in stem/ initiating cells during chemotherapy is limited. In the present study, the breast cancer cell line MDA-MB-468 was cultured with 5-fluorouracil and serially passaged. Six cell generations were collected. Semi-quantitative RT-PCR and flow cytometric techniques were used to evaluate the protein and mRNA expression of stem/initiating ...[more]

PMID: 22977582

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Project description:Through the specific identification and direct targeting of cancer stem cells (CSCs), it is believed that a better treatment efficacy of cancer may be achieved. Hence, the present study aimed to identify a CSC subpopulation from adenocarcinoma cells (A549) as a model of non‑small cell lung cancer (NSCLC). Ιnitially, we sorted two subpopulations known as the triple‑positive (EpCAM+/CD166+/CD44+) and triple‑negative (EpCAM-/CD166-/CD44-) subpopulation using fluorescence-activated cell sorting (FACS). Sorted cells were subsequently evaluated for proliferation and chemotherapy-resistance using a viability assay and were further characterized for their clonal heterogeneity, self-renewal characteristics, cellular migration, alkaline dehydrogenase (ALDH) activity and the expression of stemness-related genes. According to our findings the triple‑positive subpopulation revealed significantly higher (P<0.01) proliferation activity, exhibited better clonogenicity, was mostly comprised of holoclones and had markedly bigger (P<0.001) spheroid formation indicating a better self-renewal capacity. A relatively higher resistance to both 5‑fluouracil and cisplatin with 80% expression of ALDH was observed in the triple‑positive subpopulation, compared to only 67% detected in the triple‑negative subpopulation indicated that high ALDH activity contributed to greater chemotherapy-resistance characteristics. Higher percentage of migrated cells was observed in the triple‑positive subpopulation with 56% cellular migration being detected, compared to only 19% in the triple‑negative subpopulation on day 2. This was similarly observed on day 3 in the triple‑positive subpopulation with 36% higher cellular migration compared to the triple‑negative subpopulation. Consistently, elevated levels of the stem cell genes such as REX1 and SSEA4 were also found in the triple‑positive subpopulation indicating that the subpopulation displayed a strong characteristic of pluripotency. In conclusion, our study revealed that the triple‑positive subpopulation demonstrated similar characteristics to CSCs compared to the triple‑negative subpopulation. It also confirmed the feasibility of using the triple‑positive (EpCAM+/CD166+/CD44+) marker as a novel candidate marker that may lead to the development of novel therapies targeting CSCs of NSCLC.

Project description:BackgroundPeritoneal metastasis from colorectal cancer (CRC) carries a poor prognosis in most studies. The majority of those studies used either a single-agent or doublet chemotherapy regimen in the first-line setting.AimTo investigate the prognostic significance of peritoneal metastasis in a cohort of patients treated with triplet chemotherapy in the first-line setting.MethodsWe retrospectively evaluated progression-free survival (PFS) and overall survival (OS) in 51 patients with metastatic CRC treated in a prospective clinical trial with capecitabine, oxaliplatin, irinotecan, and bevacizumab in the first-line setting according to the presence and absence of peritoneal metastasis. Furthermore, univariate and multivariate analyses for PFS and OS were performed to assess the prognostic significance of peritoneal metastasis at the multivariate level.ResultsFifty-one patients were treated with the above triplet therapy. Fifteen had peritoneal metastasis. The patient characteristics of both groups showed a significant difference in the sidedness of the primary tumor (left-sided primary tumor in 60% of the peritoneal group vs 86% in the nonperitoneal group, P = 0.03) and the presence of liver metastasis (40% for the peritoneal group vs 75% for the nonperitoneal group, P = 0.01). Univariate analysis for PFS showed a statistically significant difference for age less than 65 years (P = 0.034), presence of liver metastasis (P = 0.046), lung metastasis (P = 0.011), and those who underwent metastasectomy (P = 0.001). Only liver metastasis and metastasectomy were statistically significant for OS, with P values of 0.001 and 0.002, respectively. Multivariate analysis showed that age (less than 65 years) and metastasectomy were statistically significant for PFS, with P values of 0.002 and 0.001, respectively. On the other hand, the absence of liver metastasis and metastasectomy were statistically significant for OS, with P values of 0.003 and 0.005, respectively.ConclusionPeritoneal metastasis in patients with metastatic CRC treated with first-line triple chemotherapy does not carry prognostic significance at univariate and multivariate levels. Confirmatory larger studies are warranted.

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Altered characteristics of cancer stem/initiating cells in a breast cancer cell line treated with persistent 5-FU chemotherapy.

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Altered characteristics of cancer stem/initiating cells in a breast cancer cell line treated with persistent 5-FU chemotherapy.

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