Impact Of Cancer Stem Cells Research Articles

The Impact of Cancer Stem Cells in Colorectal Cancer.

Despite incessant research, colorectal cancer (CRC) is still one of the most common causes of fatality in both men and women worldwide. Over time, advancements in medical treatments have notably enhanced the survival rates of patients with colorectal cancer. Managing metastatic CRC involves a complex tradeoff between the potential benefits and adverse effects of treatment, considering factors like disease progression, treatment toxicity, drug resistance, and the overall impact on the patient's quality of life. An increasing body of evidence highlights the significance of the cancer stem cell (CSC) concept, proposing that CSCs occupy a central role in triggering cancer. CSCs have been a focal point of extensive research in a variety of cancer types, including CRC. Colorectal cancer stem cells (CCSCs) play a crucial role in tumor initiation, metastasis, and therapy resistance, making them potential treatment targets. Various methods exist for isolating CCSCs, and understanding the mechanisms of drug resistance associated with them is crucial. This paper offers an overview of the current body of research pertaining to the comprehension of CSCs in colorectal cancer.

OCT-4 and DAZL expression in benign and malignant breast lesions: a prospective case control study

Purpose: The impact of cancer stem cells on breast cancer tumor biology has been poorly investigated during the last years. In the present study we sought to identify the expression of OCT-4 and DAZL, two prominent stem cell biomarkers, on malignant breast lesions. Methods: A retrospective analysis of patients that underwent simple or radical mastectomy was performed. Immunohistochemical expression of OCT-4 and DAZL was sought, and real time PCR was also applied in deparaffinized tissue samples retrieved from the pathology bank of our hospital. Results: Eighteen women aged 43-84 years old (median 57 years) were included in the present study. Of those, 10 women had invasive ductal carcinoma, 4 women had in situ ductal carcinoma and 4 women had invasive lobular carcinoma. Immunohistochemistry of tissue samples did not reveal expression of OCT-4, whereas DAZL was expressed in only 3 samples. Real time PCR was available in 13 samples as the control gene (G6PD) was not expressed in 5 samples. The 13 studied breast cell samples showed positive expression for the Oct-4 gene. In the same population the expression of DAZL varied significantly with 9 samples showing complete absence of expression and 4 providing a small signal in the last cycles, indicating barely detectable expression. The expression was significant in lobular carcinoma cases compared to cases with invasive or in situ ductal carcinoma. Conclusion: The findings of our study indicate the difficulty of retrieving reliable tissue samples following the process of deparaffinization and points towards the need for prospective case control studies that will be based on fresh tissue samples for the analysis of stem cell markers. Nevertheless, it also indicates a potentially increased expression of stemness markers in lobular carcinoma samples compared to ductal cancer cases, an observation that requires further research in the future.

The Role of Tumor Microenvironment and Impact of Cancer Stem Cells on Breast Cancer Progression and Growth

Abstract Breast cancer is not only a mass of genetically abnormal tissue in the breast. This is a well-organized system of a complex heterogeneous tissue. Cancer cells produce regulatory signals that stimulate stromal cells to proliferate and migrate; then, stromal elements respond to these signals by releasing components necessary for tumor development that provide structural support, vasculature, and extracellular matrices. Developing tumors can mobilize a variety of cell types from both local and distant niches via secret chemical factors derived from cancer cells themselves or neighboring cells disrupted by growing neo-plasm, such as fibroblasts, immune inflammatory cells, and endothelial cells. CSCs are a group of very few cells that are tumorigenic (able to form tumors) and are defined as those cells within a tumor that can selfrenew and lead to tumorigenesis. BCSCs represent a small population of cells that have stem cell characteristics and are related to breast cancer. There are different theories about the origin of BCSCs. BCSCs are responsible for breast carcinoma metastasis. Usually, there is a metastatic spread to the bones, and rarely to the lungs and liver. A phenomenon that allows BCSCs to make the transition from epithelial to mesenchymal expression and thus avoid the effect of cyto toxic agents is the epithelial-mesenchymal transition (EMT). During this process, cells change their molecular characteristics in terms of loss of epithelial characteristics taking the mesenchymal phenotype. This process plays a key role in the progression, invasion, and metastasis of breast tumors.

Establishment and characterization of a novel cancer stem-like cell of cholangiocarcinoma.

Cholangiocarcinoma (CCA) is an aggressive malignant tumor of bile duct epithelia. Recent evidence suggests the impact of cancer stem cells (CSC) on the therapeutic resistance of CCA; however, the knowledge of CSC in CCA is limited due to the lack of a CSC model. In this study, we successfully established a stable sphere-forming CCA stem-like cell, KKU-055-CSC, from the original CCA cell line, KKU-055. The KKU-055-CSC exhibits CSC characteristics, including: (1) the ability to grow stably and withstand continuous passage for a long period of culture in the stem cell medium, (2) high expression of stem cell markers, (3) low responsiveness to standard chemotherapy drugs, (4) multilineage differentiation, and (5) faster and constant expansive tumor formation in xenograft mouse models. To identify the CCA-CSC-associated pathway, we have undertaken a global proteomics and functional cluster/network analysis. Proteomics identified the 5925 proteins in total, and the significantly upregulated proteins in CSC compared with FCS-induced differentiated CSC and its parental cells were extracted. Network analysis revealed that high mobility group A1 (HMGA1) and Aurora A signaling through the signal transducer and activator of transcription 3 pathways were enriched in KKU-055-CSC. Knockdown of HMGA1 in KKU-055-CSC suppressed the expression of stem cell markers, induced the differentiation followed by cell proliferation, and enhanced sensitivity to chemotherapy drugs including Aurora A inhibitors. In silico analysis indicated that the expression of HMGA1 was correlated with Aurora A expressions and poor survival of CCA patients. In conclusion, we have established a unique CCA stem-like cell model and identified the HMGA1-Aurora A signaling as an important pathway for CSC-CCA.

Impact of Cancer Stem Cells on Therapy Resistance in Gastric Cancer

Simple SummaryTherapy resistance represents one of the major obstacles to curing cancer. Particular populations of tumor cells, known as cancer stem cells, are responsible for this resistance and, therefore, constitute key targets in the disease. In this review, we address the impact of cancer stem cells on therapy resistance in gastric cancer and we highlight the relevance of the different regulators of these cells that have been linked to resistance.Gastric cancer (GC) is the fourth leading cause of cancer death worldwide, with an average 5-year survival rate of 32%, being of 6% for patients presenting distant metastasis. Despite the advances made in the treatment of GC, chemoresistance phenomena arise and promote recurrence, dissemination and dismal prognosis. In this context, gastric cancer stem cells (gCSCs), a small subset of cancer cells that exhibit unique characteristics, are decisive in therapy failure. gCSCs develop different protective mechanisms, such as the maintenance in a quiescent state as well as enhanced detoxification procedures and drug efflux activity, that make them insusceptible to current treatments. This, together with their self-renewal capacity and differentiation ability, represents major obstacles for the eradication of this disease. Different gCSC regulators have been described and used to isolate and characterize these cell populations. However, at the moment, no therapeutic strategy has achieved the effective targeting of gCSCs. This review will focus on the properties of cancer stem cells in the context of therapy resistance and will summarize current knowledge regarding the impact of the gCSC regulators that have been associated with GC chemoradioresistance.

Impact of Cancer Stem Cells and Cancer Stem Cell-Driven Drug Resiliency in Lung Tumor: Options in Sight.

Simple SummaryLung cancer is still the most common cause of cancer death, worldwide with increasing incidence. In lung cancer management, chemotherapy alone, or combined with radiotherapy induces cell death of the tumor bulk, but not the drug-resistant cancer stem cells (CSCs) causing disease recurrence and, in some cases lead to patient death. This is due to the capacity of CSCs to self-renew and initiate tumor with high heterogeneity that adds complexity to conventional therapy. The reviewed literatures herein affirm the existence of this cell fraction in lung tumors including the CSC- related cellular and molecular mechanisms of drug resiliency. Several novel CSC inhibitors have been tested under in vitro and in vivo conditions, and in few cases in the clinical setting with encouraging results. Nevertheless, in depth investigation is essential to provide more comprehensive data as to the mode of action of these anti-CSC agents particularly, under the clinical setting.Causing a high mortality rate worldwide, lung cancer remains an incurable malignancy resistant to conventional therapy. Despite the discovery of specific molecular targets and new treatment strategies, there remains a pressing need to develop more efficient therapy to further improve the management of this disease. Cancer stem cells (CSCs) are considered the root of sustained tumor growth. This consensus corroborates the CSC model asserting that a distinct subpopulation of malignant cells within a tumor drives and maintains tumor progression with high heterogeneity. Besides being highly tumorigenic, CSCs are highly refractory to standard drugs; therefore, cancer treatment should be focused on eliminating these cells. Herein, we present the current knowledge of the existence of CSCs, CSC-associated mechanisms of chemoresistance, the ability of CSCs to evade immune surveillance, and potential CSC inhibitors in lung cancer, to provide a wider insight to drive a more efficient elimination of this pro-oncogenic and treatment-resistant cell fraction.

The Clinical Impact of Cancer Stem Cells.

Patients with cancer can go though many stages in their disease, including diagnosis, recurrence, metastasis, and treatment failure. Cancer stem cells (CSCs) are a subgroup of cells within tumors that may explain the mechanism by which tumors recur and progress. CSCs can both self-renew and produce progenitor cells of more differentiated cancer cells as well as heterogeneously demonstrate resistance and the abilities to migrate and metastasize. These "stemness" characteristics are often the result of dysregulation of one or more pathways, which can be detected by various biomarkers. Although there has been considerable laboratory research conducted on CSCs, its relevance to the practicing oncologist may seem questionable. We sought to determine the clinical impact of CSCs on patients. A systematic literature search was conducted to identify analyses containing survival information based on the expression of known CSC biomarkers in any cancer. Overall, 234 survival analyses were identified, of which 82% reported that high expression of CSC biomarker(s) resulted in poor overall survival and/or disease-free survival compared with low or no expression of the biomarker. Elevated stemness biomarker levels were also associated with decreased tumor differentiation, altered TNM stage, and increased metastasis. This analysis would suggest that CSCs have a clinical impact on patients and that practicing oncologists need to start considering incorporating CSC-targeting therapies into their patients' treatment regimens. IMPLICATIONS FOR PRACTICE: Cancer stem cells (CSCs) may occur at any stage of cancer and are implicated in the occurrence of resistance, recurrence, and metastasis. A systematic literature analysis has shown that the presence of CSCs, identified via the upregulation of stemness pathway biomarkers, results in reduced survival across all cancers studied. Several CSC-targeting agents are currently approved, and several others are in clinical trials. Future treatment regimens will likely include CSC-targeting agents to enable the elimination of these holdouts to current therapies.

Identifying and targeting cancer stem cells in leiomyosarcoma: prognostic impact and role to overcome secondary resistance to PI3K/mTOR inhibition

BackgroundLeiomyosarcoma (LMS) is one of the most frequent soft tissue sarcoma subtypes and is characterized by a consistent deregulation of the PI3K/mTOR pathway. Cancer stem cells (CSCs) have been poorly studied in soft tissue sarcomas. In this study, we aimed to evaluate the association between CSCs, the outcome of LMS patients, and the resistance to PI3K/mTOR pathway inhibition.MethodsWe investigated the relationships between aldehyde dehydrogenase 1 (ALDH1) expression, a cancer stem cell marker, and the outcome of LMS patients in two independent cohorts. We assessed the impact of CSCs in resistance to PI3K/mTOR pathway inhibition using LMS cell lines, a xenograft mouse model, and human tumor samples.ResultsWe found that enhanced ALDH1 activity is a hallmark of LMS stem cells and is an independent prognostic factor. We also identified that secondary resistance to PI3K/mTOR pathway inhibition was associated with the expansion of LMS CSCs. Interestingly, we found that EZH2 inhibition, a catalytic component of polycomb repressive complex which plays a critical role in stem cell maintenance, restored sensitivity to PI3K/mTOR pathway inhibition. Importantly, we confirmed the clinical relevance of our findings by analyzing tumor samples from patients who showed secondary resistance after treatment with a PI3Kα inhibitor.ConclusionsAltogether, our findings suggest that CSCs have a strong impact on the outcome of patients with LMS and that combining PI3K/mTOR and EZH2 inhibitors may represent a promising strategy in this setting.

Immunological and Clinical Impact of Cancer Stem Cells in Vulvar Cancer: Role of CD133/CD24/ABCG2-Expressing Cells.

Cancer stem cells (CSCs) are tumour-initiating cells with self-renewal properties and chemo/radio-resistance. Regulatory T-cells (Tregs) influence CSCs through several mechanisms. In different solid tumours, the presence of both cell populations correlated with poor survival. In vulvar cancer, little is known regarding biological markers able to predict patient prognosis. We investigated the presence and clinical impact of CSCs and infiltrating Treg in primary vulvar cancer. Paraffin-embedded tissue specimens derived from 43 patients with vulvar cancer were analyzed by immunohistochemistry for the expression of prominin-1 (CD133), CD24, ATP-binding cassette sub-family G member 2 (ABCG2) (CSC markers) and forkhead box protein P3 (FOXP3) (Treg marker). CD133 expression correlated with younger age at diagnosis (p<0.01), lymph-node metastasis (p<0.05) and larger tumour diameter (p<0.05). CD133+ tumours showed a high FOXP3+ T-cell infiltration. Overall survival and progression-free survival were not influenced by the expression of the analyzed biomarkers. In vulvar cancer, CSCs were more frequently expressed in younger aged patients and those with aggressive disease. Their presence was also associated with high Treg infiltration, which contributes to the generation of an immunosuppressive milieu.

Iron induces cancer stem cells and aggressive phenotypes in human lung cancer cells.

Evidence has accumulated in support of the critical impact of cancer stem cells (CSCs) behind the chemotherapeutic failure, cancer metastasis, and subsequent disease recurrence and relapse, but knowledge of how CSCs are regulated is still limited. Redox status of the cells has been shown to dramatically influence cell signaling and CSC-like aggressive behaviors. Here, we investigated how subtoxic concentrations of iron, which have been found to specifically induce cellular hydroxyl radical, affected CSC-like subpopulations of human non-small cell lung carcinoma (NSCLC). We reveal for the first time that subchronic iron exposure and higher levels of hydroxyl radical correlated well with increased CSC-like phenotypes. The iron-exposed NSCLC H460 and H292 cells exhibited a remarkable increase in propensities to form CSC spheroids and to proliferate, migrate, and invade in parallel with an increase in level of a well-known CSC marker, ABCG2. We further observed that such phenotypic changes induced by iron were not related to an epithelial-to-mesenchymal transition (EMT). Instead, the sex-determining region Y (SRY)-box 9 protein (SOX9) was substantially linked to iron treatment and hydroxyl radical level. Using gene manipulations, including ectopic SOX9 overexpression and SOX9 short hairpin RNA knockdown, we have verified that SOX9 is responsible for CSC enrichment mediated by iron. These findings indicate a novel role of iron via hydroxyl radical in CSC regulation and its importance in aggressive cancer behaviors and likely metastasis through SOX9 upregulation.

Stem cell expression profile in hepatocellular carcinoma, small cell dysplasia, and cirrhosis

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide with various etiologies and its incidence still continues to increase. Tumors with progenitor/stem cell (P/SC) immunophenotype are currently the main focus of interest. Human hepatic P/SCs are located in ductal plates in fetal and neonatal livers and they remain relatively constant throughout life. Enhanced self-renewal level of normal hepatic P/SCs serves as an early event in hepatocarcinogenesis. Approximately 40% of HCCs arise from P/SCs and these cells have a critical role in development and progression of HCC. Thus, CD133 expression was found to be upregulated during early liver restoration. In spite of the increasing evidence of the impact of cancer stem cells (CSCs) in hepatocarcinogenesis, the role of CSCs in the sequence of cirrhosis (Crh)-dysplastic nodules (DN)-HCC is still not clear. In our recent research, we investigated the expression rate and staining patterns of CD133 and CD90 in Crh, small cell dysplasia, and HCC. We also evaluated the relationship between the expression rates of CSC markers and the etiology of liver diseases. Among the P/SC markers, we like to attract more attention to CD133 and CD90. Both CD133 and CD90 expressions were higher in poorly differentiated HCC cases than well differentiated ones. According to the etiology, we found that the highest staining rate for CD133 in HCC cases developed in a cirrhotic background with chronic hepatitis B and D co-infection. The highest rate for CD90 was determined in HCC cases with chronic hepatitis C. Since Crh is the end-stage of chronic injury with continuing regeneration, detection of accompanying P/SC activation by CSC markers in suspicious nodules may suggest the initiation of early phases of hepatocarcinogenesis. Some other immunophenotypical features such as Glypican 3, heat shock protein-70, and glutamine synthetase stainings are also being used to diagnose precursor lesions. Facing the emerging concept of personalized treatment strategy, it is obvious that the studies in hepatocarcinogenesis related to the theory of CSCs will provide new ideas on genesis, development, and metastasis of HCC and will bring new insights for the diagnosis and treatment of these tumors.

Abstract 4931: Cancer stem cells in solid tumors: Symmetric division, niche size, and invasive tumor morphology

Abstract In recent years cancer stem cells have been identified as a minor subpopulation in numerous solid tumors that drives tumor initiation, development and metastasis. Although cancer stem cells have yet to be reliably isolated, populations enriched for tumor-initiating cells give an indication of the order of magnitude of the stem cells niche within primary tumors. Here we develop and discuss the predictions of a simple theoretical model of cancer stem cells and tumor growth dynamics. We evaluate the impact of cancer stem cell symmetric/asymmetric division and progeny cancer cell proliferation capacity on tumor progression and morphology. The model predicts that the frequency of symmetric cancer stem cell division determines the resulting stem cell pool size, and that the symmetric division frequency and the stem cell fraction are both typically small, consistent with the cancer stem cell hypothesis. At the same time, we show that intrinsic competition for space and environmental confinement can lead to an increasing stem cell fraction over time despite a fixed, low symmetric division probability. These findings offer a novel explanation for the apparent differences in reported stem cell numbers for different tumors as well as tumors of the same organ, and thus challenging the hypothesis of a fixed stem cell ratio for different tumors. The pivotal role of stem cell division strategies and stem cell ratio on spatio-temporal morphology evolution and self-organizing tumor patterning is discussed. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4931. doi:10.1158/1538-7445.AM2011-4931

Stem Cells

Stem cells offer the potential of new therapies for previously untreatable diseases. This session focuses on different aspects of stem cells from embryonic stem cells to adult stem cells and the biology and therapeutic impact of cancer stem cells.

Cancer Stem Cells: On the Verge of Clinical Translation

Researchers have long studied malignant tumors using experimental techniques that assume that cancers are composed of identical cells; however, growing evidence indicates that cancers are composed of functionally heterogeneous cells maintained by a stem cell-like population. Identification of tumor-initiating, or cancer stem cells, has been largely guided by principles established for normal stem cells. Cancer stem cells must be capable of initiating tumors when transplanted into immunodeficient mice, and the resulting tumors must replicate the heterogeneity of the original tumor. Demonstration of the ability to self-renew, a key feature of stem cells, is achieved through serial passage of tumors in xenohosts. Given their potential roles in tumor initiation, maintenance, and metastasis, the impact of cancer stem cells on the practice of medicine is likely to be profound.