Cancer Stem Cells In Patients Research Articles

Safety and Effectiveness of Perioperative Hyperthermic Intraperitoneal Chemotherapy with Gemcitabine in Patients with Resected Pancreatic Ductal Adenocarcinoma: Clinical Trial EudraCT 2016-004298-41.

Despite the improvement in therapies, pancreatic cancer represents one of the most cancer-related deaths. In our hypothesis, we propose that Hyperthermic Intraperitoneal Chemotherapy with gemcitabine after pancreatic cytoreductive surgery could reduce tumor progression by reducing residual neoplastic volume and residual pancreatic cancer stem cells. A randomized trial involving 42 patients. All patients were diagnosed with pancreatic ductal adenocarcinoma. Group I: R0 resection. Group II. R0 resection and HIPEC with gemcitabine (120 mg/m2 for 30 min). Effectiveness was measured with analysis of overall survival, disease-free survival, distant recurrence, locoregional recurrence, and measuring of pancreatic cancer stem cells (EpCAM+CXCR4+CD133+). From 2017 to 2023, 63 patients were recruited for our clinical trial; 21 patients were included in each group, and 21 were excluded. Locoregional recurrence, p-value: 0.022, was lower in the experimental group. There were no significant differences between the two groups in hospital mortality, perioperative complications, or hospital costs. We found a significant decrease in pancreatic cancer stem cells in patients in the experimental group after treatment, p -value of 0.018. The use of HIPEC with gemcitabine after surgery in patients with resectable pancreatic ductal adenocarcinoma reduces locoregional recurrence and may be associated with a significant decrease in pancreatic cancer stem cells.

Study of MicroRNA 203 and Its Target Genes (Survivin, Cyclin-D) in Circulating Liver Cancer Stem Cells in Patients with Chronic Hepatitis C with and without HCC

Abstract Background Hepatitis C virus (HCV) infection is a significant cause of morbidity and mortality, infecting more than 180 million people worldwide. Chronic viral infection is one of the most common causes of hepatic fibrosis, distortion of the hepatic architecture, and ultimate progression to cirrhosis of the liver. HCV infection inflames the liver which, if unmanaged, will inevitably result in fibrosis and then progress to cirrhosis which has many co-morbid complications such as hepatocellular carcinoma (HCC). HCC is an aggressive tumor usually involving late stage liver cancers when diagnosed. Although significant progress regarding the treatment options for HCC has been made in recent years, poor prognosis remains a problem because of late diagnosis and drug resistance, making recurrence almost inevitable. Objective to compare level of miRNA 203 and its target genes (Survivin, Cyclin-D) in circulating liver cancer stem cells in patients with chronic hepatitis C with and without H.C.C. Patients and Methods This study was conducted in co-operation between Gastroenterology and Hepatology Department, Ain-Shams University and the Gastroenterology and Hepatology Department, Theodor Bilharz Research Institute “between” April 2021 to October 2021.It included total participants of 80 divided to 4 GrousGroup A (HCV group): twenty patients infected with HCV without liver cirrhosis.Group B (LC group): twenty patients infected with HCV with liver cirrhosis.Group C (HCC group): twenty patients infected with HCV with HCC.Control group: twenty normal populations. Results our study demonstrated that the level of miRNA 203 showed statistically significant difference between all study groups with lowest level was found in HCC group and highest level was in control group with statistically significant decrease in HCC group than LC and other groups. The study also demonstrated that circulating level of Survivn shows significant increase in HCC group than other study groups. With no significant changes in its level between non HCC groups (Control, HCV and LC groups).The circulating Cyclin D level showed significant increase in HCC group than other study groups, With statistically significant increase in its level in LC group than control and non-cirrhotic HCV group. The study markers (miRNA 203, Survivn and Cyclin D) showed no significant relation between their levels in HCC patients and AFP level. Also, no significant relation was established between (miRNA 203, Survivn and Cyclin D) and PVT, number of focal lesions, largest diameter of the lesion or BCLC. Conclusion miRNA 203 level in circulating CSCs showed significant changes according to the stage of HCV related disease with lowest level is seen in HCC patients.Survivin level in circulating CSCs showed significant increase in HCC patients with no significant difference between other groups, and this indicates that changes in its level is highly specific for malignant transformation.Cyclin D level in circulating CSCs showed significant increase in HCC patiens than other study groups, with increase in its level in LC patients than control and non-cirrhotic HCV patients, and this indicates that the changes in its level start with cirrhosis process. No relation was established between (circulating miRNA 203, Survivn and Cyclin D) and AFP, PVT, number of focal lesions, largest diameter of the lesion or BCLC.

Analysis of Circulating Tumor and Cancer Stem Cells Provides New Opportunities in Diagnosis and Treatment of Small Cell Lung Cancer.

Current methods for diagnosis and treatment of small cell lung cancer (SCLC) have only a modest efficacy. In this pilot study, we analyzed circulating tumor cells (CTCs) and cancer stem cells (CSCs) in patients with SCLC to search for new diagnostic and prognostic markers and novel approaches to improve the treatment of the disease. In other forms of lung cancer, we showed a heterogeneity of blood CTCs and CSCs populations, as well as changes in other cell populations (ALDH+, CD87+CD276+, and EGF+Axl+) in smokers. A number of CTCs and CSCs in patients with SCLC have been shown to be resistant to chemotherapy (CT). High cytotoxic activity and resistance to apoptosis of reprogrammed CD3+CD8+ T-lymphocytes (rTcells) in relation to naive CD3+CD8+ T-lymphocytes was demonstrated in a smoking patient with SCLC (Patient G) in vitro. The target for rTcells was patient G’s blood CSCs. Reprogramming of CD3+CD8+ T-lymphocytes was carried out with the MEK1/2 inhibitor and PD-1/PD-L1 pathway blocker nivolumab. The training procedure was performed with a suspension of dead CTCs and CSCs obtained from patient’s G blood. The presented data show a new avenue for personalized SCLC diagnosis and targeted improvement of chemotherapy based on the use of both CTCs and CSCs.

Clinicopathological significances of PLOD2, epithelial-mesenchymal transition markers, and cancer stem cells in patients with esophageal squamous cell carcinoma.

Background:To examine the expression level of procollagen-lysine2-oxoglutarate 5-dioxygenase 2 (PLOD2) in esophageal squamous cell carcinoma (ESCC) and analyze its correlation with clinicopathological parameters, in order to explore the mechanism of PLOD2 in regulating invasion and metastasis of ESCC.Methods:Immunohistochemistry was used to detect the expression level of PLOD2 in tumor tissues and paired adjacent tissues of 172 patients with ESCC, and the relationship between PLOD2 expression and clinicopathological parameters was analyzed. The deposition of collagen fibers in tumor was detected by Sirius red staining. The correlation between tumor stem cells and epithelial–mesenchymal transition (EMT) markers ZEB1 was analyzed by multivariate logistic regression.Results:The expression level of PLOD2 in tumor tissues of patients with ESCC (70.35%, 121/172) was significantly higher than that in paired adjacent tissues (29.65%, 51/172; P < .01). The positive expression rate of PLOD2 in ESCC was related to T classification, lymph node metastasis, and pathological tumor node metastasis of a tumor. The expression rates of ZEB1, CD44, and CD133 in ESCC were correlated with T classification, lymph node metastasis and pathological tumor node metastasis. Scarlet red staining showed that collagen fiber deposition in ESCC tissues with high expression of PLOD2 was significantly higher than that in tissues with low expression of PLOD2 (P < .01). A positive correlation was observed between the expression of PLOD2 and CD133, PLOD2 and CD44, and PLOD2 and N-cadherin (P < .01). Moreover, a negative correlation was noted between the expression of PLOD2 and E-cadherin (P < .01). The combined expression of PLOD2 and ZEB1 were independent prognostic factors for the total survival time of patients with ESCC.Conclusion:PLOD2 is highly expressed in ESCC and is closely related to tumor invasion and metastasis. The mechanism of PLOD2 for promoting invasion and metastasis of ESCC may be related to activation of the EMT signaling pathway to promote EMT and tumor stem cell transformation.

PD-L1 is overexpressed on tumorspheres cultured from circulating cancer stem cells in patients with breast cancer.

3052 Background: Circulating cancer cells, and in particular their very rare subpopulation, circulating cancer stem cells (cCSCs), are responsible for recurrence and metastasis. The exact role of cCSCs in escape of cancer from immunosurveillance is still unknown, but recent studies revealed that enhanced PDL-1 expression in cancer stem cells is linked to immune evasion and could crucially contribute to the maintenance of CSC self-renewal. Understanding the mechanisms behind this PDL-1 overexpression in cancer stem cells is critical for developing more effective anti-PD-1/PD-L1 therapy. Therefore the aim of the study was to determine the number of tumorspheres and expression of PD-L1 on tumorspheres cultured from cCSC in breast cancer patients. Methods: 110 patients with breast cancer in different stages of disease were included in this study. The determination of circulating cancer stem cells was performed using the sphere-forming assay. Additionally anti-PDL-1 antibody staining was applied to examine PDL-1 expression on breast tumorspheres. Results: We have developed an innovative in vitro platform for detection of cCSCs from peripheral blood of cancer patients. The number of tumorspheres increased significantly with tumor progression and aggressiveness of primary tumor. Patients with metastatic disease had statistically more tumorspheres as compared to patients without metastasis (30 vs 10/100µl blood, p &lt; 0.05). Patients with multiple metastasis had more tumorspheres compared to patients with single metastases (60 vs 30/100µl blood, p &lt; 0.05). The number of tumorspheres was positively correlated with Ki-67, Her2 status and grade score in primary breast tumors. We observed high PDL-1 expression and their considerable heterogeneity in enriched tumorspheres. Conclusions: The number of tumorspheres cultured from peripheral blood directly reflects aggressiveness and proliferation capacity of primary tumor. The presence of tumorspheres with expression of PDL-1 might suggest their immunregulatory potential. Better understanding of the interaction between cCSCs and tumor immunology may help to identify strategies to eradicate the minor subpopulation that escapes conventional therapy attack, thus providing a solution to the problem of drug resistance and metastasis.

Understanding autophagy role in cancer stem cell development

Cancer stem cells (CSCs) are a small subpopulation of immature cells located in the tumor mass. These cells are responsible for tumor development, proliferation, resistance and spreading. CSCs are characterized by three unique features: the ability to self-renew, differentiation and tumor formation. CSCs are similar to stem cells, but they differ in the malignant phenotype. CSCs become immortal and survive harsh environmental conditions such as hypoxia, starvation and oxidative stress. However, this harsh tumor microenvironment induces the activation of autophagy, which further increases the CSCs stemness profile, and all these features further increase tumorigenicity and metastasis capacity. Autophagy is induced by the extracellular and cellular microenvironment. Hypoxia is one of the most common factors that highly increases the activity of autophagy in CSCs. Therefore, hypoxia-induced autophagy and CSCs proliferation should be elucidated in order to find a novel cure to defeat cancer cells (CSCs and non-CSCs). The remaining challenges to close the gap between the laboratory bench and the development of therapies, to use autophagy against CSCs in patients, could be addressed by adopting a 3D platform to better-mimic the natural environment in which these cells reside. Ultimately allowing to obtain the blueprints for bioprocess scaling up and to develop the production pipeline for safe and cost-effective autophagy-based novel biologics.

Prognostic Significance of Cancer Stem Cell Markers in Patients With Salivary Gland Carcinomas.

Cancer stem cells (CSCs) are a small group of cells resistant to therapy and play a major role in tumor progression, recurrence, and poor clinical outcomes of patients. This study aimed to evaluate the association of CSC markers with clinicopathologic features and survival in patients with salivary gland carcinomas (SGCs). The medical records of 48 patients affected by mucoepidermoid carcinoma (MEC) and 47 patients with adenoid cystic carcinoma (AdCC) were reviewed retrospectively. SOX2, CD133, and CD44 expression was appraised by immunohistochemistry and statistically analyzed to weigh the correlation between these markers and patients' clinicopathologic features and tumor outcomes. In AdCC patients showing poor outcomes, a trend toward a high expression of CD133 and CD44 and low expression of SOX2 was observed, while in MEC patients experiencing the same outcomes, there was a trend toward a high expression of CD44 and low expression of CD133 and SOX2. Only the increase of MEC histopathologic grade was statistically significant with decreased SOX2 expression. Distant metastasis in AdCC patients, tumor grade, lymph node involvement, and local recurrence in MEC patients had significant correlations with patients' survival. Besides the significant association between low SOX2 expression and higher grades of MEC, we found no statistically significant correlation between the studied CSC markers and patients' survival or clinicopathologic features. Therefore, a larger sample size with long-term follow-up is beneficial for thorough investigations toward the main role of CSCs in patients with SGCs.

New Perspectives in Different Gene Expression Profiles for Early and Locally Advanced Non-Small Cell Lung Cancer Stem Cells.

IntroductionLung cancer is one of the most common cancers in the world, causing over 1.7 million deaths in 2018. Thus far, no effective treatments against lung cancer for advanced stages have been found. For early stages, although surgery is considered the gold standard treatment, 30–55% of patients develop recurrence within the first 5 years of surgery. Our aim is to assess whether cancer stem cells (CSC) display overexpression of a pool of genes that were previously identified for adenocarcinoma recurrence in patients with early and locally advanced stages of non-small cell lung cancer (NSCLC).MethodsThis cross-sectional study was carried out by harvesting surgical tumor specimens obtained from patients harboring early (I-II) and locally advanced (IIIA) stages of NSCLC. For each patient, cell sorting was performed to identify and isolate the ALDHhigh (CSC) and ALDHlow (cancer cells) populations. The mRNA expressions of 31 recurrence-related genes (target genes) in both ALDHhigh and ALDHlow populations were then assessed and compared.ResultsSurgical specimens were obtained from 22 patients harboring NSCLC. Sixteen (51.6%) out of 31 recurrence-related genes were significantly overexpressed in ALDHhigh cells in the early stages and 9 (29.0%) were overexpressed in the locally advanced stages of NSCLC. Overall, the relative mRNA expressions for these recurrence-related genes were higher in early-stage patients. The average fold change, considering all 31 recurrence-related genes together, was 4.5 (95% CI = 3.1-6.3) in early-stage patients and 1.6 (95% CI = 1.2-2.2) in locally advanced-stage patients.ConclusionsOur study represents the first attempt toward identifying genes associated with recurrence that are overexpressed in cancer stem cells in patients with early and locally advanced stages of NSCLC. This finding may contribute to the identification of new target therapies tailored for NSCLC stages.

Quantitative Changes in the Population of Cancer Stem Cells after Radiation Exposure in a Dose of 10 Gy as a Prognostic Marker of Immediate Results of the Treatment of Squamous Cell Cervical Cancer.

Prognostic significance of the proportion of cancer stem cells in cervical scrapings from 38 patients with uterine cervical cancer before treatment and after irradiation in a total dose of 10 Gy was assessed for immediate results of radio- and combined chemoradiotherapy evaluated by the degree of tumor regression in 3-6 months after the treatment. Cancer stem cells were detected as cells with CD44+CD24low immunophenotype by flow cytometry. The proportion of cancer stem cells in patients with the complete tumor regression decreased by on average 2.2±1.1% after irradiation, while in patients with partial regression this indicator increased by on average 3.3±2.3% (p=0.03). Multiple regression analysis revealed two independent indicators affecting tumor regression: the stage of the disease (which is quite expected) and change in the proportion of cancer stem cells after the first irradiation sessions (R=0.60, p<0.002 for the model in the whole). The proportion of cancer stem cells before the treatment did not have prognostic significance.

Downregulation of DAPK1 promotes the stemness of cancer stem cells and EMT process by activating ZEB1 in colorectal cancer

Cancer stem cells (CSCs) and epithelial-mesenchymal transition (EMT) play an important role in the metastasis and chemoresistance in the context of colorectal cancer (CRC). Downregulation of death associated protein kinase 1 (DAPK1) may promote metastasis and chemoresistance of cancer cells through various mechanisms. However, the association between DAPK1 and CSCs or EMT has not been explored. In this study, we demonstrated that DAPK1 was associated with elevated stemness of CSCs in patients with CRC. Silencing of DAPK1 in CRC cell lines promoted the metastasis and chemoresistance due to increased stemness of CSCs and enhanced mesenchymal phenotype, an effect that was mediated via activation of the transcription factor, zinc finger E-box binding homeobox 1 (ZEB1). Blockade of this signaling pathway attenuated the stemness of CSCsand rescued the EMT process. DAPK1-ZEB1 may lie at the interface of TGF-β and WNT pathways and participate in both CSCs and EMT process. Targeted therapies aimed at DAPK1-ZEB1 pathway may inhibit the chemoresistance and metastasis of CRC. KEY MESSAGES: Downregulation of DAPK1 promotes chemoresistance and metastasis of CRC. Inhibition of DAPK1 promotes the stemness of cancer stem cells and EMT process. DAPK1-ZEB1 may lie at the interface of TGF-β and WNT pathways. DAPK1-ZEB1 participates in both CSCs and EMT process.

Whole exome sequencing approach to analysis of the origin of cancer stem cells in patients with head and neck squamous cell carcinoma.

Head and neck squamous cell carcinoma (HNSCC) is a global public health problem, which increases in prevalence every year. Evidence brings up that small populations of stem cells, the cancer stem cells (CSC), are responsible for tumour initiation, tumorigenesis, progression, and metastasis. These cells play a crucial role in cancer development and treatment response, but the origin of CSCs remains unclear. In this research, we have sequenced the entire exome of the three different groups of cells of primary squamous cell carcinoma tumour from different patients, with the aim to understand their main genetic changes and to elucidate the possible origin of tumour cells and tumour stem cells. We performed a whole exome sequencing in the germinal line, tumour cells, and CSC ALDH+ samples from four HNSCC patients. An analysis pipeline was used to filter, score, rank, and prioritize candidate variants according to its effect on protein structure and phylogenetic conservation using available information on pathways and protein function databases. Results showed variations in genes involved in oncogenic pathways and shed light on the evolution model of the CSC and tumour cells for each patient in which stem cells (CS) triggered the formation of CSC and these in turn become tumour cells. These findings support the idea that it is possible to identify in each individual patient if the CS are of tumour origin or vice versa, thus being possible a more personalized treatment.

Targeting glypican-4 overcomes 5-FU resistance and attenuates stem cell-like properties via suppression of Wnt/β-catenin pathway in pancreatic cancer cells.

The existences of cancer stem cells in patients with pancreatic cancer are considered as pivotal factors contributing to chemoresistance and disease relapse. Glypican-4 (GPC4) is one of the members of the glypicans family, which underlies human congenital malformations and multiple diseases. However, its potential biological function in pancreatic cancer still remains elusive. In this study, we are the first to demonstrate that GPC4 was involved in 5-fluorouracil (5-FU) resistance and pancreatic cancer stemness through comprehensive bioinformatical analysis. Functional experiments showed that knockdown of GPC4 sensitized pancreatic cancer cells to 5-FU and attenuated stem cell-like properties. In terms of mechanism research, knockdown of GPC4 suppressed the activation of Wnt/β-catenin pathway and its downstream targets. Furthermore, the expression of GPC4 was significantly upregulated in pancreatic cancer tissues compared with normal tissues and remarkably correlated with patients' overall survival according to the data derived from the Cancer Genome Atlas database. Taken together, our results suggest that GPC4 is a key regulator in chemoresistance and pancreatic cancer stemness. Thus, targeting GPC4 may serve as a promising strategy for pancreatic cancer therapy.

The prognostic significance of breast cancer stem cells in patients with metastatic breast cancer.

e12565Background: Breast cancer ranks as the first malignancy affecting females.There is increasing evidence that this cancer is originated in and maintained by a small population of undifferentiat...

Evaluation of anti-cancer stem cell activity of the anti-DLL4 antibody MEDI0639 in a phase I clinical trial of SCLC.

e20093 Background: Small-cell lung cancer (SCLC) is a very aggressive lung cancer with a high metastatic potential. Many patients with SCLC initially respond to standard-of-care therapy but have rapid recurrence. The high metastatic potential and rapid recurrence may be driven by cancer stem cells (CSCs). MEDI0639 is a human monoclonal antibody that selectively binds to DLL4 and inhibits DLL4-Notch receptor signaling. Preclinical studies have demonstrated that DLL4 blockade reduces tumor cell proliferation and cancer stem cell frequency in various tumors. The objective of this study was to evaluate effect of MEDI0639 treatment on CSCs in patients with SCLC. Methods: Nine SCLC patients were enrolled in this phase I single-agent study of MEDI0639. Pre- and post-treatment tumor biopsies were collected at screening and Day 15 of cycle one. CSC frequency and CSC gene expression in tumor samples were analyzed by DepArray and RT-PCR, respectively. Tumor CSC activity was also assessed by an ex vivo sphere formation assay. Circulating tumor cells (CTCs) and circulating CSCs were measured by CellSearch at different time points. Results: The tumor CSC activity was suppressed ( > 30%) after treatment with MEDI0639 in 4 of 8 patients with evaluable tumor biopsy samples. Three of the 8 patients also demonstrated > 50% reductions tumor CSC count after MEDI0639 treatment. Expression levels of CSC genes (CD133, EZH2, and ASCL1) were decreased after MEDI0639 treatment in 3 of 7 patients with adequate tumor RNA samples. In 2 patients, CTC and circulating CSC counts were decreased to 0, concurrent with suppression of CSC gene expression and CSC count or activities in tumor samples, after 1 or 2 cycles of MEDI0639 treatment. Conclusions: Our data suggests that MEDI0639 may suppress CSC counts and activities in a subpopulation of SCLC patients and thus warrants a further study with more patients. Clinical trial information: NCT01577745.

Abstract POSTER-BIOL-1332: Molecular, cellular and clinical interaction between MDSC and ovarian cancer stemness

Abstract Myeloid derived suppressor cells (MDSCs) and cancer stem cells (CSCs) are important cellular components in the cancer microenvironment, and may affect cancer phenotype and patient outcome. The nature of MDSCs and their interaction with CSCs in ovarian carcinoma are unclear. We examined the interaction between MDSCs and CSCs in patients with ovarian carcinoma. We demonstrate that MDSCs inhibit T cell activation, enhance CSC gene expression, sphere formation and cancer metastasis. MDSCs trigger microRNA101 expression in cancer cells; microRNA101 subsequently represses the co-repressor gene C-terminal binding protein-2 (CtBP2), and CtBP2 directly targets stem cell core genes resulting in increased cancer cell stemness, and increasing metastatic and tumorigenic potential. Increased MDSC density and tumor microRNA101 levels, and decreased tumor CtBP2 expression independently predict poor survival. Collectively, the work identifies a novel immune associated cellular, molecular and clinical network involving MDSCs/microRNA101/CtBP2/stem cell core genes, which extrinsically controls cancer stemness and impacts patient outcome. Citation Format: Ilona Kryczek, Tracy X. Cui, Lili Zhao, Linda Vatan, Wojciech Szeliga, Rebecca Liu, Weiping Zou. Molecular, cellular and clinical interaction between MDSC and ovarian cancer stemness [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr POSTER-BIOL-1332.

P0061 Identification of CD44, α2β1-integrin, and CD133 expressing prostate cancer stem cells in patients from South Korea with prostate cancer

Background Existing therapies for prostate cancer eradicate most cells within a tumour. However, most patients develop androgen-independent disease that cannot be cured. Prostate cancer cells originate from rare stem cells responsible for maintenance of the tumour. Identification of a prostate cancer stem cell provides a useful target from which to develop therapies targeted at these stem cells. Methods Four patients with prostate cancer were included. Their mean age was 72.3 (SD ± 6.6) years. PSA (ng/ml), Gleason score, node involvement, or metastasis in patients were recorded (88.1/7 [4+3], none or bone; 77.7/9 [5+4], iliac node, or bone; 31.4/9 [4+5], none or bone; 299/9 [5+4], iliac node or bone, respectively). Hormonal therapy of prostate cancer was given as a luteinising hormone-releasing hormone agonist and anti-androgen agent. A transurethral resection of the prostate was done and prostate tissue was obtained. Paraffin embedded serial sections (4 μm) were processed for prostate cancer tissue using immunofluorescent staining. Anti-CD133 antibody (1:10, clone 293C3), anti- α 2 β 1-integrin antibody (clone AK-7; TCS), and anti-CD44 (clone G44-26) were used to identify the prostate cancer cells. Stained sections of tissue were then examined under a Olympus laser confocal fluorescence microscope. Findings CD44, α 2 β 1-integrin, and CD133 expressing cancer stem cells were randomly located throughout acini of prostate cancer. High levels of PSA, Gleason score, or lymph node involvement of prostate cancer was not predicted by the presence of cancer stem cells. Interpretation We identified CD133, CD44, and α 2 β 1-integrin expressing cancer stem cells in patients in South Korea with prostate cancer.

Stem cells increase in numbers in perinecrotic areas in human renal cancer.

Developing strategies to overcome resistance to sunitinib is a major challenge in human renal cell carcinoma (RCC). We hypothesized that sunitinib-induced tumor necrosis-associated hypoxia could interact with renal cancer stem cells in patients with metastatic RCC. We studied tissue samples from 7 patients with primary metastatic RCC, before and after sunitinib treatment, and from six xenograft models derived from human RCC. Two xenograft models were responders to sunitinib, the four others were nonresponders. CD133/CXCR4-coexpressing cells derived from the two responder xenograft models were used for in vitro studies. In the seven primary RCCs, we identified a significantly larger number of CD133/CXCR4-coexpressing cells in perinecrotic versus perivascular areas. Their numbers also significantly increased after treatment, in perinecrotic areas. We reproduced these clinical and pathologic results in all six RCC xenograft models with again a preferential perinecrotic distribution of CD133-expressing cells. Necrosis occurred at day 7 in the two responder models treated with sunitinib, whereas it occurred at day 21 in the untreated controls and in the four nonresponder models. Strikingly, when we studied the six RCC xenograft models at the time necrosis, whether spontaneous or sunitinib-induced, occurred, necrosis area correlated with stem-cell number in all 120 xenografted RCCs. When studied under experimental hypoxia, the number of CD133/CXCR4-coexpressing cells and their tumorigenic potency increased whereas their sensitivity to sunitinib decreased. In human RCC, sunitinib was able to generate resistance to its own therapeutic effect via induced hypoxia in perinecrotic areas where cancer stem cells were found in increased numbers.

A phase II trial of maintenance ADAPT therapy targeting colon cancer stem cells in patients with metastatic colorectal cancer.

TPS3650 Background: Presence of cancer stem cells (CSC) appears to be the chief cause of drug resistance to cytotoxic or targeted chemotherapy. Experimental models suggest that these resistant canc...

Prognostic significance of ALDH1A1-positive cancer stem cells in patients with locally advanced, metastasized head and neck squamous cell carcinoma.

Aldehyde dehydrogenase 1 (ALDH1A1) has now been recognized as a cancer stem(-like) cells (CSCs) marker in various tumors including head and neck squamous cell carcinoma (HNSCC). The objective of this study was to examine the expression of ALDH1A1 in patients with locally advanced, metastasized HNSCC and to determine its prognostic value. Human papillomavirus genotypes and expression of ALDH1A1, Twist1, and p16 were analyzed in specimens of 81 patients with primary HNSCC and 49 lymph node metastases. Patient clinicopathologic and follow-up data were analyzed. Expression of ALDH1A1 was observed in 38 (46.9 %) of 81 primary tumors and 26 (53 %) of 49 lymph node metastases, respectively. Notably, the expression of ALDH1A1 was correlated significantly with poor tumor differentiation grade (p = 0.011). Interestingly, ALDH1A1 was observed co-expressed with Twist1 in primary tumor and lymph node metastases. Multivariate analysis showed that ALDH1A1 expression predicted poor prognosis in patients with HNSCC (p = 0.011) and the subgroup of oropharyngeal squamous cell carcinoma (p = 0.001). In the patient cohort with advanced, metastasized tumors, ALDH1A1 was identified as independent predictor of overall survival in both groups. Our results provide evidence for the prognostic value of ALDH1A1 as a CSC marker in patients with locally advanced, metastasized HNSCC.

ITRAQ-Based Proteomic Analysis of Polyploid Giant Cancer Cells and Budding Progeny Cells Reveals Several Distinct Pathways for Ovarian Cancer Development

Polyploid giant cancer cells (PGCCs) are a morphologically distinct subgroup of human tumor cells with increased nuclear size or multiple nuclei, but they are generally considered unimportant because they are presumed to be nondividing and thus nonviable. We have recently shown that these large cancer cells are not only viable but also can divide asymmetrically and yield progeny cancer cells with cancer stem-like properties via budding division. To further understand the molecular events involved in the regulation of PGCCs and the generation of their progeny cancer cells, we comparatively analyzed the proteomic profiles of PGCCs, PGCCs with budding daughter cells, and regular control cancer cells from the HEY and SKOv3 human ovarian cancer cell lines with and without CoCl2. We used a high-throughput iTRAQ-based proteomic methodology coupled with liquid chromatography-electrospray ionization tandem mass spectroscopy to determine the differentiated regulated proteins. We performed Western blotting and immunohistochemical analyses to validate the differences in the expression patterns of a variety of proteins between PGCCs or budding PGCCs and regular cancer cells identified by iTRAQ approach and also a selected group of proteins from the literature. The differentially regulated proteins included proteins involved in response to hypoxia, stem cell generation, chromatin remodeling, cell-cycle regulation, and invasion and metastasis. In particular, we found that HIF-1alpha and its known target STC1 are upregulated in PGCCs. In addition, we found that a panel of stem cell-regulating factors and epithelial-to-mesenchymal transition regulatory transcription factors were upregulated in budding PGCCs, whereas expression of the histone 1 family of nucleosomal linker proteins was consistently lower in PGCCs than in control cells. Thus, proteomic expression patterns provide valuable insight into the underlying mechanisms of PGCC formation and the relationship between PGCCs and cancer stem cells in patients with ovarian cancers.