The Role of Stem and Circulating Cells in Cancer Metastasis
Department of Dermatology, Epithelial Pipeline of the Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, California, USA.Journal of Surgical Oncology (Impact Factor: 3.24). 05/2011; 103(6):555-7. DOI: 10.1002/jso.21807
While many solid tumors have been reported to contain stem cell-like cells termed cancer stem cells, the case for a melanoma stem cell has been debated over the last few years. Herein, we summarize current knowledge of melanoma-initiating cells and provide an update on recently gained knowledge regarding cancer stem cells and melanoma.
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ABSTRACT: Angiopoietin-2 (Ang2) has been shown highly expressed in resected human pancreatic carcinoma samples, and has tightly combination with tumor angiogenesis, but the role in metastasis of it is less clear. We were, therefore, interested in exploring the effects of Ang2 silencing on the invasion and metastasis of pancreatic carcinoma. Lentivirus (LV)-mediated Ang2 small hairpin RNA (LV-RNAi) and mock lentivirus (LV-NC) were transfected into pancreatic carcinoma cell line MIA PaCa-2. Groups were designed in this study: the control group (MIA PaCa-2 cells), the LV-NC group (cells transfected with the LV-NC), the LV-RNAi-KD1 group (cells transfected with LV-RNAi of knock down sequence (1) and the LV-RNAi-KD2 group (cells transfected with LV-RNAi of knock down sequence (2). Boyden chamber transwell assay was used to detect the cell invasion change. The protein levels of Ang2, MMP-2, and MMP-9 gene and mRNA level of MMP-2, MMP-9 were detected by Western blot and real-time polymerase chain reaction, respectively. Orthotopic pancreatic carcinoma xenotransplantation model were successfully built with MIA PaCa-2 cells injection. After treatment with intraperitoneal injection of LV-RNAi-KD2 (LV-RNAi), mice growth, liver function test, tumor volume and peritoneal metastatic numbers were observed and counted. Moreover, expression of Ang2, MMP-2, MMP-9 were measured by immunohistochemistry. Ang2 expression were successfully knocked down in two LV-RNAi groups, especially in the LV-RNAi-KD2group. Compared with the control group and the LV-NC group, the mRNA and protein level of MMP-2 gene were downregulated significantly in LV-RNAi groups, also the invasion cell number decreased in boyden chamber transwell assay after LV-RNAi transfection. Meanwhile, no obvious MMP-9 gene expression changes were found among all the groups. LV-RNAi injection inhibited pancreatic carcinoma metastasis and growth in vivo by downregulating the expression of MMP-2 not MMP-9. Most importantly, LV-mediated gene therapy with Ang2 knockdown exhibited almost no toxicity in vivo. These findings demonstrate that Ang2 gene silencing exert an anti-metastasis effect in vitro and in vivo, and Ang2 targeted gene therapy has the potential to serve as a novel way for pancreatic carcinoma treatment.
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ABSTRACT: Although the concept of cancer stem cells (CSCs) is well-accepted for many tumors, the existence of such cells in human melanoma has been the subject of debate. In this study, we demonstrate the existence of human melanoma cells that fulfill the criteria for CSCs (self-renewal and differentiation) by serially xenotransplanting cells into nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mice. These cells possess high aldehyde dehydrogenase (ALDH) activity with ALDH1A1 and ALDH1A3 being the predominant ALDH isozymes. ALDH-positive melanoma cells are more tumorigenic than ALDH-negative cells in both NOD/SCID mice and NSG mice. Biological analyses of the ALDH-positive melanoma cells reveal the ALDH isozymes to be key molecules regulating the function of these cells. Silencing ALDH1A by siRNA or shRNA leads to cell cycle arrest, apoptosis, decreased cell viability in vitro, and reduced tumorigenesis in vivo. ALDH-positive melanoma cells are more resistant to chemotherapeutic agents and silencing ALDH1A by siRNA sensitizes melanoma cells to drug-induced cell death. Furthermore, we, for the first time, examined the molecular signatures of ALDH-positive CSCs from patient-derived tumor specimens. The signatures of melanoma CSCs include retinoic acid (RA)-driven target genes with RA response elements and genes associated with stem cell function. These findings implicate that ALDH isozymes are not only biomarkers of CSCs but also attractive therapeutic targets for human melanoma. Further investigation of these isozymes and genes will enhance our understanding of the molecular mechanisms governing CSCs and reveal new molecular targets for therapeutic intervention of cancer. STEM Cells2012;30:2100-2113.
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ABSTRACT: B7-H3, a member of the B7-family molecules, plays an important role in adaptive immune responses. In addition, B7-H3 is also expressed in several types of human cancers and is correlated with the poor outcome of cancer patients. However, its exact role in cancer is not known. In the present study, we compared B7-H3 expression in normal pancreas and pancreatic cancer tissue specimens, and determined the effects of low B7-H3 expression on the human pancreatic cancer cell line Patu8988 using lentivirus-mediated RNA interference. B7-H3 expression in pancreatic specimens was determined by enzyme-linked immunosorbent assay (ELISA). A Patu8988 cell line with low B7-H3 expression was established by lentivirus-mediated RNA interference to investigate the effect of B7-H3 on cell proliferation, migration and invasion in vitro. By establishing subcutaneous transplantation tumor and orthotopic transplantation pancreatic cancer mouse models, the effect of B7-H3 on cell proliferation, migration and invasion was studied in vivo. B7-H3 in tissue samples was significantly higher in the pancreatic cancer group than in the normal pancreas group (mean ± SD, 193.6±9.352 vs. 87.74±7.433 ng/g; P<0.0001). B7-H3 knockdown by RNA interference decreased cell migration and Transwell invasion up to 50% in vitro. No apparent impact was observed on cell proliferation in vitro. In the subcutaneous transplantation tumor mouse model, the tumor growth rate was reduced by the knockdown of B7-H3. In the orthotopic transplantation pancreatic cancer mouse model, the effect of inhibiting metastasis by knocking down B7-H3 was assessed in terms of the average postmortem abdominal visceral metastatic tumor weight. This demonstrated that inhibition of B7-H3 expression reduced pancreatic cancer metastasis in vivo. In conclusion, B7-H3 is aberrantly expressed in pancreatic cancer. In addition to modulating tumor immunity, B7-H3 may have a novel role in regulating pancreatic tumor progression.
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