Circulating Cancer Stem Cells Research Articles

Circulating cancer stem cells: a novel prognostic predictor of hepatocellular carcinoma.

Not only tumor progression but also metastasis are the major causes of mortality from a wide range of cancers, including hepatocellular carcinoma (HCC). In general, tumor cells frequently leave the primary tumor and form metastatic lesions in distant organs. It has been believed that tumor infiltration of blood vessels at the primary tumor site is responsible for the dissemination of tumor cells and the formation of metastatic lesions in distant organs.

Circulating Tumor Cells in Hepatocellular Carcinoma: Detection Techniques, Clinical Implications, and Future Perspectives

Hepatocellular carcinoma (HCC) is a primary liver cancer with a huge challenge in terms of its complex etiology and its management. The fact that the most common site of early tumor recurrence in liver transplantation for HCC is the transplanted allograft strongly suggests that circulating tumor cells (CTCs) are really an active source of HCC metastasis or recurrence. In the past decade, with the tremendous progress in the technology of CTC detection, there is convincing evidence that CTCs have great potential as a marker for metastatic disease and poor prognosis in patients with a malignancy. Currently some interesting and encouraging results have been achieved in HCC CTC detection, although the knowledge about its clinical relevance in HCC is lagging behind other major tumor types. Here we will review existing and developing methodologies for CTC detection, discuss future perspectives, and describe the potential clinical impact of the identification and molecular characterization of CTC subset or circulating cancer stem cells in HCC patients. Particular attention is given to the results based on the HCC CTC study.

Prognostic Value of Putative Circulating Cancer Stem Cells in Patients Undergoing Hepatic Resection for Colorectal Liver Metastasis

Although surgery is the gold standard treatment of hepatic metastasis from colorectal cancer (CRC), many patients ultimately die of their disease. We tested the hypothesis that the detection of circulating tumor cells (CTC) might identify patients at high risk of dying of disease recurrence after apparently radical liver surgery. We considered 50 patients undergoing radical surgery for liver-confined hepatic metastasis from CRC. The expression of a panel of cancer-related genes, as assessed by quantitative real-time PCR, was used to detect CTC in the peripheral blood of these patients immediately before surgery. Survival analysis was performed by the Cox regression model. Univariate analysis of the expression levels of CD133 (a marker of colon cancer stem cells) and survivin (an antiapoptotic factor) resulted in statistically significant association with patient survival [hazard ratio (HR) 2.7, 95% confidence interval (CI) 1.9-3.7, P < 0.0001; and hazard ratio 2.1, 95% CI 1.4-3.2, P < 0.0001, respectively]. Remarkably, multivariate analysis found that only the transcriptional amount of CD133 resulted in statistical significance (HR 2.6, 95% CI 1.9-3.6, P < 0.0001), indicating that this biomarker can independently predict the survival of these patients. CD133-positive CTC may represent a suitable prognostic marker to stratify the risk of patients who undergo liver resection for CRC metastasis, which opens the avenue to identifying and potentially monitoring the patients who are most likely to benefit from adjuvant treatments.

Prediction of Posthepatectomy Recurrence of Hepatocellular Carcinoma by Circulating Cancer Stem Cells

To investigate whether circulating cancer stem cells (CSCs) of hepatocellular carcinoma (HCC) can predict its recurrence after hepatectomy. HCC recurrence frequently occurs within the first year after hepatectomy, probably due to circulating tumor cells that have been shed from the primary tumor before hepatectomy. Because CSCs are more likely to initiate tumor growth than mature cancer cells, a high level of circulating CSCs may be a hint for HCC recurrence. Multicolor flow cytometry was used to detect the number of circulating CSCs (CD45CD90CD44) in the peripheral circulation of 82 HCC patients 1 day before hepatectomy. The patients were monitored by CT or MRI for recurrence every 3 months. Forty-one (50%) patients had recurrence after a median follow-up period of 13.2 months (range, 1.3-57.1 months). Patients with recurrence had a higher median level of circulating CSCs than patients without recurrence (0.02% vs. 0.01%; P < 0.0001). Circulating CSCs > 0.01% predicted intrahepatic recurrence (relative risk 3.54; 95% CI, 1.41-8.88; P = 0.007) and extrahepatic recurrence (relative risk 10.15; 95% CI, 3-34.4; P = 0.0002). Patients with >0.01% circulating CSCs had a lower 2-year recurrence-free survival rate (22.7% vs. 64.2%; P < 0.0001) and overall survival rate (58.5% vs. 94.1%; P = 0.0005) than patients with ≤0.01% circulating CSCs. On multivariable analysis, circulating CSCs > 0.01%, tumor stage and tumor size were independent factors predicting recurrence-free survival. Circulating CSCs predicted posthepatectomy HCC recurrence with high accuracy. They may be the target of eradication in the prevention of posthepatectomy HCC metastasis and recurrence.

Faithful Markers of Circulating Cancer Stem Cells: Is CD133 Sufficient for Validation in Clinics?

TO THE EDITOR: We read with great interest the recent article by Iinuma et al published in Journal of Clinical Oncology. The authors describe an innovative strategy to identify circulating cancer stem cells (C-CSCs) from blood samples in patients with radically resected nonmetastatic colorectal cancer (CRC). In particular, the study suggests a prognostic value for the identification of CD133, cytokeratins (CKs) and carcinoembryonicm antigen (CEA) mRNA in selected patients with Dukes’ stage B and C. This large study (which included a validation cohort) could pave the way to better prognostic stratification, ultimately optimizing the use of adjuvant chemotherapy. In addition, similar assays may be more accurate than classical response evaluation criteria when testing cancer stem cell (CSC) –specific therapies in the advanced disease setting, as underlined in the accompanying editorial. As we have recently suggested, CSCspecific assays may constitute the backbone of next-generation pharmacogenomics.

Identifying Circulating Tumor Stem Cells That Matter: The Key to Prognostication and Therapeutic Targeting

TO THEEDITOR: We read with interest the article by Iinuma et al 1 that describes their study examining the clinical significance of cancer stem cells in the peripheral blood of patients with colorectal cancer (CRC). The defining characteristics of a circulating cancer stem cell (CTSC) are its capacity for self-renewal and for initiation of distant metastases; some of these cells are also resistant to traditional chemo- therapy. 2,3 The concept that circulating tumor stem cells can be iden- tified and targeted is attractive and has major diagnostic, prognostic, and therapeutic implications for patients with metastatic cancer. However, the identification of authentic CTSCs continues to be a challenge because of the lack of a clear understanding of the biologic heterogeneity of tumor stem-cell populations and also because of the lack of characterization of surface markers that predict clinically im- portant subsets of CTSCs, such as those with aggressive malignant potential or drug resistance.

Colonic Stem Cell Biomarkers for the Detection of Circulating Cancer Stem Cells

Colonic Stem Cell Biomarkers for the Detection of Circulating Cancer Stem Cells

Early relapse in a rectal cancer patient: Possible implication of circulating cancer stem cell

Early relapse in a rectal cancer patient: Possible implication of circulating cancer stem cell

Nanotechnology‐based molecular photoacoustic and photothermal flow cytometry platform for in‐vivo detection and killing of circulating cancer stem cells

In-vivo multicolor photoacoustic (PA) flow cytometry for ultrasensitive molecular detection of the CD44+ circulating tumor cells (CTCs) is demonstrated on a mouse model of human breast cancer. Targeting of CTCs with stem-like phenotype, which are naturally shed from parent tumors, was performed with functionalized gold and magnetic nanoparticles. Results in vivo were verified in vitro with a multifunctional microscope, which integrates PA, photothermal (PT), fluorescent and transmission modules. Magnet-induced clustering of magnetic nanoparticles in individual cells significantly amplified PT and PA signals. The novel noninvasive platform, which integrates multispectral PA detection and PT therapy with a potential for multiplex targeting of many cancer biomarkers using multicolor nanoparticles, may prospectively solve grand challenges in cancer research for diagnosis and purging of undetectable yet tumor-initiating cells in circulation before they form metastasis.

Identification of local and circulating cancer stem cells in human liver cancer

Increasing evidence has revealed the importance of cancer stem cells (CSCs) in carcinogenesis. Although liver CSCs have been identified in hepatocellular carcinoma (HCC) cell lines, no data have shown the presence of these cells in human settings. The present study was designed to delineate CSCs serially from HCC cell lines, human liver cancer specimens to blood samples, using CD90 as a potential marker. The number of CD90(+) cells increased with the tumorigenicity of HCC cell lines. CD45(-)CD90(+) cells were detected in all the tumor specimens, but not in the normal, cirrhotic, and parallel nontumorous livers. In addition, CD45(-)CD90(+) cells were detectable in 90% of blood samples from liver cancer patients, but none in normal subjects or patients with cirrhosis. A significant positive correlation between the number of CD45(-)CD90(+) cells in the tumor tissues and the number of CD45(-)CD90(+) cells in the blood samples was identified. CD90(+) cells sorted from cell lines and CD45(-)CD90(+) cells from the tumor tissues and blood samples of liver cancer patients generated tumor nodules in immunodeficient mice. Serial transplantation of CD90(+) cells from tumor xenografts generated tumor nodules in a second and subsequently third batch of immunodeficient mice. Treatment of CD90(+) CSCs with anti-human CD44 antibody induced cell apoptosis in a dose-dependent manner. Identification of CD45(-)CD90(+) CSCs in both tumor tissues and circulation suggests that CD45(-)CD90(+) could be used as a marker for human liver cancer and as a target for the diagnosis and therapy of this malignancy.