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Most stem cell transplants are performed to treat neoplasms. Yet many patients survive the transplant but die from cancer recurrence post-transplant. The incorporation of post-transplant immunotherapy offers the potential for enhanced antitumor efficacy.
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Glioma stem-like cells constitute one of the potential origins of gliomas, and therefore, their elimination is an essential factor for the development of efficient therapeutic strategies. Cannabinoids are known to exert an antitumoral action on gliomas that relies on at least two mechanisms: induction of apoptosis of transformed cells and inhibition of tumor angiogenesis. However, whether cannabinoids target human glioma stem cells and their potential impact in gliomagenesis are unknown. Here, we show that glioma stem-like cells derived from glioblastoma multiforme biopsies and the glioma cell lines U87MG and U373MG express cannabinoid type 1 (CB(1)) and type 2 (CB(2)) receptors and other elements of the endocannabinoid system. In gene array experiments, CB receptor activation altered the expression of genes involved in the regulation of stem cell proliferation and differentiation. The cannabinoid agonists HU-210 and JWH-133 promoted glial differentiation in a CB receptor-dependent manner as shown by the increased number of S-100beta- and glial fibrillary acidic protein-expressing cells. In parallel, cannabinoids decreased the cell population expressing the neuroepithelial progenitor marker nestin. Moreover, cannabinoid challenge decreased the efficiency of glioma stem-like cells to initiate glioma formation in vivo, a finding that correlated with decreased neurosphere formation and cell proliferation in secondary xenografts. Gliomas derived from cannabinoid-treated cancer stem-like cells were characterized with a panel of neural markers and evidenced a more differentiated phenotype and a concomitant decrease in nestin expression. Overall, our results demonstrate that cannabinoids target glioma stem-like cells, promote their differentiation, and inhibit gliomagenesis, thus giving further support to their potential use in the management of malignant gliomas.
Telomeres are TTAGGG repetitive motifs found at the ends of vertebrate chromosomes. In humans, telomeres are protected by shelterin, a complex of six proteins (de Lange [2005] Genes Dev. 19: 2100-2110). Since (Müller [1938] Collecting Net. 13: 181-198; McClintock [1941] Genetics 26: 234-282), their function in maintaining chromosome stability has been intensively studied. This interest, especially in cancer biology, stems from the fact that telomere dysfunction is linked to genomic instability and tumorigenesis (Gisselsson et al. [2001] Proc. Natl. Acad. Sci. USA 98: 12683-12688; Deng et al. [2003] Genes Chromosomes Cancer 37: 92-97; DePinho and Polyak [2004] Nat. Genetics 36: 932-934; Meeker et al. [2004] Clin. Cancer Res. 10: 3317-3326). In the present overview, we will discuss the role of telomeres in genome stability, recent findings on three-dimensional (3D) changes of telomeres in tumor interphase nuclei, and outline future avenues of research.
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PURPOSE: Breast cancer has a poorer prognosis among black women than among white women. This review was conducted to determine whether this disparity reflects the direct impact of race on likelihood of cure or on time to death from breast cancer or stems from the interaction of race with tumor stage and patient age. PATIENTS AND METHODS: We analyzed data from 115,838 patients with localized (node-negative) and regionally metastatic (node-positive) breast cancer from the Surveillance, Epidemiology, and End-Results (SEER) Program of the National Cancer Institute. Parametric analysis was used to determine the independent prognostic value of age, stage, and race. Linear regression and distribution analyses were also used to examine the interaction of these covariates. RESULTS: The prevalence of regionally metastatic disease, relative to localized disease, declined with increased age among white patients and those classified as "other," but remained relatively constant among black patients. Parametric analysis showed a smaller cured fraction and shorter time to death when patients with regional disease were compared with those with localized disease. A similar disparity was found when black patients were compared with those classified as white or other. CONCLUSION: Age and race have a significant association with tumor stage. In addition, our data show that race has an independent impact on the clinical course of breast cancer and diminishes both the likelihood of cure and time to death among uncured patients.
BACKGROUND: Autologous transplantation is increasingly used to treat epithelial ovarian cancer. However, it is not clear which patients may benefit. OBJECTIVE: To determine overall and progression-free survival and factors associated with favorable outcome after autotransplantation for ovarian cancer. DESIGN: Observational cohort study. SETTING: 57 centers reporting to the Autologous Blood and Marrow Transplant Registry (ABMTR). PATIENTS: 421 women who received transplants between 1989 and 1996. INTERVENTIONS: High-dose chemotherapy using diverse regimens with hematopoietic stem-cell rescue. MEASUREMENTS: Primary outcomes were progression-free survival and overall survival. Multivariate analyses using Cox proportional hazards regression considered the following factors: age, Karnofsky performance score, initial stage, histologic characteristics, previous therapy, remission status, extent of disease, graft source, transplant regimen, and year of transplantation. RESULTS: Most patients had extensive previous chemotherapy. Forty-one percent had platinum-resistant tumors, and 38% had tumors at least 1 cm in diameter. Only 34 patients (8%) received transplants as part of initial therapy. The probability of death within 100 days was 11% (95% CI, 8% to 14%). Two-year progression-free survival was 12% (CI, 9% to 16%), and 2-year overall survival was 35% (CI, 30% to 41%). Younger age, Karnofsky performance score of at least 90%, non-clear-cell disease, remission at transplantation, and platinum sensitivity were associated with better outcomes. Progression-free and overall survival were 22% (CI, 12% to 33%) and 55% (CI, 42% to 66%), respectively, for women with a high Karnofsky performance score and non-clear-cell, platinum-sensitive tumors. CONCLUSIONS: Some subgroups of patients with ovarian cancer seem to have good outcomes after autotransplantation, although several biases may have affected these observations. Phase III trials are needed to compare such outcomes with outcomes of conventional chemotherapy.
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One hundred women with metastatic breast cancer (MBC) underwent high-dose chemotherapy with autologous stem cell rescue at our institution beginning in 1986. The patients underwent induction chemotherapy from June 1986 to December 1993. Patients who showed stable or responsive disease underwent HDC with cyclophosphamide (CY) at 7.5 g/m2 and thiotepa (TPA) at 675 mg/m2 or the same doses of CY and TPA with carmustine at 450 mg/m2. The source of stem cell rescue was either BM alone, BM and G-CSF-mobilized peripheral blood progenitor cells (PBPC) or PBPC alone if patients had BM involvement with MBC. With a median follow-up of 62 months (range 1-109 months), median survival from reinfusion was 16 months with a 5-year survival of 19+/-4%. The median event-free survival (EFS) was 8 months with a 5-year EFS of 11+/-3%. Patients achieving a complete response to induction therapy showed a higher 5-year EFS from reinfusion of 31+/-8% in contrast to 3+/-3% (P = 0.006) for patients who achieved a partial response to induction therapy prior to HDC. Marrow involvement or source of stem cell rescue did not affect outcome. Our mature results confirm that high-dose chemotherapy with autologous stem cell rescue can confer a prolonged DFS in a subset of women with MBC. However, the high rate of relapse remains a universally disturbing problem in this patient population.
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RT-PCR is increasingly used for the detection of minimal residual disease in solid tumors. Carcinoembryonic antigen (CEA) RT-PCR seemed to be highly specific for detection of tumor cells when tested on PBMC. A very high frequency of RT-PCR amplification product for CEA in PBSC from breast cancer patients mobilized with G-CSF was found. However, this result contrasted with tumor cell detection by immunocytochemistry (ICC) which showed no correlation with RT-PCR results. In addition, CEA mRNA was amplified in most G-CSF-mobilized PBSC samples derived from patients with hematological malignancies and from healthy donors of allogeneic stem cells, although no circulating epithelial cells could be demonstrated by ICC. CEA RT-PCR expression was observed in PBMC from healthy individuals incubated in vitro with G-CSF. These data suggest that CEA transcription can be induced by G-CSF, resulting in a loss of specificity of CEA RT-PCR for tumor cell detection in PBMC. We conclude, CEA RT-PCR may not be recommended to detect tumor cell contamination in peripheral blood from patients treated with G-CSF. This may have implications on tumor cell detection by RT-PCR in tissues where endogenous or exogenous growth factors may induce the transcription of CEA or other genes.
Research on different types of stem cells is of major interest because of its apparent very promising therapeutic prospects, such as for Parkinson's and Alzheimer's disease, spinal cord injuries, stroke, diabetes, cardiac failure, liver failure, cartilage injuries, severe blood diseases, cancer etc. Stem cells can be derived from different sources: adult tissue, foetal tissues, and from in vitro fertilised embryos. Depending on their origin they have varying capacity to multiply and differentiate to other cell types. It is at present not possible to predict which types of cells will be best suitable for various therapeutic situations. Embryonic stem cells have been shown capable of differentiating into all the different tissues and cell types of the body, but they cannot form a new individual. Because of the ethics question involved, The European Group on Ethics on Science and New Technologies for the European Commission and Parliament (EGE), and the Ethics Committee of the Nordic Council of Ministers have prepared reports and given guidelines for research on stem cells. According to the guidelines, every country should regulate the research. Only embryos, which cannot be used in infertility treatment, and have been donated for research, can be used. Creation of embryos solely for research purposes, including somatic cell nuclear transfer, is not regarded as acceptable for the time being. Both partners of the donating couple have to sign an informed consent document. Ongoing research in Sweden is well in line with these European and Nordic recommendations.
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Breast cancer cells have been detected in autologous blood stem cell collections of early stage breast cancer patients, but their clinical significance is undefined. From October 1993 to August 1998, 32 consecutive Stage II breast cancer patients with 4-9-positive nodes underwent stem cell apheresis. The patients were treated with cyclophosphamide 1.75 gm/m(2), etoposide 400 mg/m(2) and cisplatin 50 mg/m(2) daily for 3 days, followed by infusion of the autologous cells. Cytospins of cells from each apheresis collections and from an aliquot of three pooled collections were examined for cytokeratin expression using an immunocytochemical assay. The cells were considered positive for tumor if at least one cell with tumor morphology stained positively for cytokeratin. Negative aliquots were confirmed with RT-PCR. Six patients (19%) had positive collections. In total, 24 patients (75%) were disease free a median of 61 (30-86) months after transplant. Eight patients relapsed at a median of 17 (8-27) months after transplant. Four of the disease-free patients and two of the relapsed patients had positive apheresis collections. There was no significant correlation between the presence of detectable tumor cells in the graft product and outcome.
Given that each year in the United States 180,000 new cases of breast cancer are diagnosed, with about 44,000 women succumbing to the disease, and that breast cancer is the second leading cause of cancer-related death in women, it is clear that existing therapy fails a large number of patients. Recently, a number of novel strategies have been developed in attempts to improve survival. These include agents used at very high dose requiring stem cell support. High-dose chemotherapy (HDC) with hematopoietic stem cell transplantation (HSCT), most frequently in the form of peripheral blood progenitor cell transplantation (PBPCT), is an highly active treatment approach in appropriate patients and the current data relating to this modality will be reviewed here. This article will attempt to place the recent randomized studies in perspective, to highlight the strengths and limitations of the data, and to offer some thoughts on future directions for the field.