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PubMed2004

Stem cells, plasticity and cancer - uncomfortable bed fellows.

Stem cell research is a vibrant and rapidly moving field of science that investigates self-renewing cells in the adult and embryo. Two debates currently exist in the stem cell field concerning the transcriptional redirection of stem cell differentiation and fate, and the reorganization of cell commitment through nuclear reprogramming caused by cell fusion and nuclear transfer. The recent Keystone Symposium in Colorado on stem cells, organised by Fiona Watt and Leonard Zon, brought together both leading and upcoming researchers in the field to explore stem cell biology and these issues.

Adult↗
PubMed2005

[Nonmyeloablative stem cell transplantation as cancer immunotherapy].

Allogeneic hematopoietic stem cell transplantation (HSCT) is used for the treatment of selected haematological malignancies. Its curative potential is based on two different mechanisms, i.e. the conditioning regimen and the graft-versus-host immunologic reactions. However, because of its toxicity, it is restricted to younger and fitter patients. These observations led several groups to set up new (less toxic) transplant protocols. These transplants are called nonmyeloablative HSCT or minitransplants. These are feasible with a relatively low transplant-related mortality even in patients up to 70 years. In addition, strong anti-tumor responses are observed in several haematological malignancies.

Hematologic Neoplasms↗
PubMed2004

Stem cells and cancer; the polycomb connection.

Proteins from the Polycomb group (PcG) are epigenetic chromatin modifiers involved in cancer development and also in the maintenance of embryonic and adult stem cells. The therapeutic potential of stem cells and the growing conviction that tumors contain stem cells highlights the importance of understanding the extrinsic and intrinsic circuitry controlling stem cell fate and their connections to cancer.

Animals↗
PubMed2003

Impact of chemotherapy regimen and hematopoietic growth factor on mobilization and collection of peripheral blood stem cells in cancer patients.

Various chemotherapy regimens, combined with recombinant human granulocyte colony-stimulating factor(rhG-CSF) or recombinant granulocyte-macrophage CSF (rhGM-CSF) are used in cancer patients to mobilize and collect peripheral blood stem cells (PBSC). In this retrospective study, we evaluated and compared the efficacy of such regimens in 262 patients with different types of malignant diseases. The following chemotherapy regimens were applied: ifosfamide-etoposide-cisplatin or bleomycin (n = 96; mainly patients with testicular cancer); ifosfamide-etoposide plus or minus cytosine arabinoside (Ara-C) or vincristine (VCR)(n = 52; mainly patients with lymphoma); cyclophosphamide-anthracycline (n = 53; mainly patients with breast cancer); intermediate to high dose (ID-HD) cyclophosphamide (n = 37; mainly patients with breast or ovarian cancer. or multiple myeloma; and others (n = 24). rhG-CSF or rhGM-CSF, each at an average daily dose of 5 microg/kg body weight, were used in 166 and 96 patients, respectively. The study evaluated and compared the efficacy of these two cytokines. In patients receiving rhG-CSF, CD34+ cells could be collected earlier (median: day 14 versus day 16) and there was a significantly higher white blood cell count (WBC)(median 11,350 versus 5550/microl) and CD34+ cell count (median 88 versus 43/microl) at the start of apheresis, and a significantly higher CD34+ cell yield (median 7.4 x 10(6) versus 4.6 x 10(6)/kg) than in patients who receivedrhGM-CSF. Among the various chemotherapeutic regimens used, each combined with rhG-CSF, ifosfamide-etoposide plus or minus Ara-C or VCR mobilized a significantly higher number of CD34+ cells (median 119/microl) and produced a significantly higher harvest of these cells (median 13 x 10(6)/kg) than cyclophosphamide-anthracycline (median 87/microl and 7 x 10(6)/kg, respectively) or ID-HD cyclophosphamide (median 59/microl and 5 x I 0(6)/kg, respectively). Ifosfamide-etoposide plus or minus Ara-C or VCR was also superior to ifosfamide-etoposide-cisplatin or bleomycin (median 78/microl and 9 x 10(6)/kg, respectively), but at borderline significance. The outcome of PBSC mobilization and collection appeared to be negatively influenced by the number of relapses before the current salvage treatment. These data indicate that mobilization and collection of PBSCstrongly depend on the type of hematopoietic growth factor and chemotherapeutic regimen used. The data further show rhG-CSF is a more effective growth factor than rhGM-CSF and ifosfamide-etoposide-based regimens, particularly ifosfamide-etoposide plus or minus Ara-C or VCR, are highly effective regimens in mobilizing and collecting CD34+ cells.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2005

Epstein-barr virus-related gastric adenocarcinoma: an early secondary cancer post hemopoietic stem cell transplantation.

BACKGROUND & AIMS: Epstein-Barr virus (EBV) infection has been associated with some cases of gastric cancer. METHODS: We studied a case of early onset gastric adenocarcinoma after nonmyeloablative hematopoietic stem cell transplantation for myeloma in a 56-year-old man. RESULTS: The development of gastric adenocarcinoma was preceded by severe graft-versus-host disease (GVHD) necessitating strong immunosuppression, which resulted in an intense reactivation of EBV infection. Three sequential gastric biopsy examinations performed at 100, 130, and 150 days after hematopoietic stem cell transplantation showed gastritis, dysplasia, and adenocarcinoma, respectively. There was no evidence of Helicobacter pylori infection. Quantitative polymerase chain reaction for circulating EBV showed a surge of EBV DNA peaking at the time of gastritis, followed by a gradual decrease afterward with adequate control of GVHD and tailing of immunosuppression. In situ hybridization for EBV-encoded early small RNA showed absence of EBV in the gastritis specimen, but the presence of EBV in the dysplastic and carcinoma specimens. Aberrant promoter methylation of E-cadherin was observed only in the carcinoma specimens, showing that infection with EBV preceded E-cadherin methylation. CONCLUSIONS: Mucosal damage caused by GVHD, immunosuppression, and EBV reactivation combined to lead to EBV infection of the gastric cells and initiation of carcinogenesis, suggesting this case to be a genuine EBV-related opportunistic malignancy post-transplantation. An interesting proposition is that this case also might reflect a compacted timeline of events in EBV-related gastric cancers developing in immunocompetent patients.

Adenocarcinoma↗
PubMed2005

Liver cancer: the role of stem cells.

Studies of aggregation chimaeras and X-linked polymorphisms strongly suggest that liver tumours are derived from single cells (monoclonal), but the important question is, which cell? Stem cell biology and cancer are inextricably linked. In continually renewing tissues such as the gut mucosa and epidermis, where a steady flux of cells occurs from the stem cell zone to the terminally differentiated cells that are imminently to be lost, it is widely accepted that cancer is a disease of stem cells, since these are the only cells that persist in the tissue for a sufficient length of time to acquire the requisite number of genetic changes for neoplastic development. In the liver the identity of the founder cells for the two major primary tumours, hepatocellular carcinoma and cholangiocarcinoma, is more problematic. The reason for this is that no such obvious unidirectional flux occurs in the liver, although it is held that the centrilobular hepatocytes may be more differentiated (polyploid) and closer to cell senescence than those cells closest to the portal areas. Moreover, the existence of bipotential hepatic progenitor cells, along with hepatocytes endowed with longevity and long-term repopulating potential suggests there may be more than one type of carcinogen target cell. Cell proliferation at the time of carcinogen exposure is pivotal for 'fixing' any genotoxic injury into a heritable form, thus any proliferative cell in the liver can be susceptible to neoplastic transformation. Hepatocytes are implicated in many instances of hepatocellular carcinoma, direct injury to the biliary epithelium implicates cholangiocytes in some cases of cholangiocarcinoma, while hepatic progenitor cell/oval cell activation accompanies many instances of liver damage irrespective of aetiology, making such cells very likely carcinogen targets. Of course, we must qualify this assertion by stating that many carcinogens are both cytotoxic and cytostatic, and that hepatic progenitor cell proliferation may be merely a bystander effect of this toxicity. An in-depth discussion of causes of cancer in the liver is beyond the scope of this review, but infectious agents (e.g. hepatitis B and C viruses) play a major role, not just in transactivating or otherwise disrupting cellular proto-oncogenes (hepatitis B virus), but also in causing chronic inflammation (hepatitis C and B viruses). Sustained epithelial proliferation in a milieu rich in inflammatory cells, growth factors and DNA-damaging agents (reactive oxygen and nitrogen species--produced to fight infection), will lead to permanent genetic changes in proliferating cells. Up-regulation of the transcription factor NF-kappaB in transformed hepatocytes, through the paracrine action of TNF-alpha from neighbouring endothelia and inflammatory cells, may be critical for tumour progression given the mitogenic and antiapoptotic properties of proteins encoded by many of NF-kappaB's target genes.

Animals↗
PubMed2000

Purging of human breast cancer cells from stem cell products with an adenovirus containing p53.

Tumor cell contamination of stem cell products can contribute to tumor relapse following high-dose chemotherapy and stem cell rescue. Numerous techniques have been used to remove the tumor cells from stem cell products with the objective of prolonging relapse-free survival. However, to date these techniques have been relatively ineffectual and/or toxic to hematopoietic stem and progenitor cells. The differential infectivity of adenovirus (Adv) vectors for breast cancer cells, compared with hematopoietic cells, has suggested that Adv-p53 might provide an effective purging strategy. To facilitate the use of Adv-p53 as a clinical strategy, we undertook studies to determine the parameters necessary for optimal stem cell product purging. The parameters studied were the particle number to nucleated cell ratio, the duration of coincubation, the incubation volume, and the presence or absence of hematopoietic progenitor cells. We have found that these parameters are interdependent and conclude that a 4-hour coincubation with an Adv-p53 particle to nucleated cell ratio of 2000:1 with 2 x 10(8) nucleated cells/mL is optimal for tumor cell purging. Furthermore, this appeared to be a safe procedure, with total loss of clonogenic growth of breast cancer cells as well as no significant effect on progenitor cell function as determined by granulocyte-macrophage colony-forming unit assays.

Adenoviridae↗
PubMed2005

Wnt, stem cells and cancer in the intestine.

The intestinal epithelium is a self-renewing tissue which represents a unique model for studying interconnected cellular processes such as proliferation, differentiation, cell migration and carcinogenesis. Although the stem cells of the intestine have not yet been physically characterized or isolated, data over the past decade have strongly implicated the Wnt/beta-catenin signalling pathway in their maintenance and progression to cancer. This review will (i) describe the distinctive features of the intestinal epithelium in relation to stem-cell function, (ii) illustrate the major genetic alterations that can lead to cancer, and (iii) show how Wnt/beta-catenin signalling controls homoeostasis in this tissue.

Animals↗
PubMed1998

Minimal Residual Cancer Detection in Hematopoietic Stem Cell Products and Its Prognostic Significance in Patients With Breast Cancer, Lymphoma, or Multiple Myeloma.

BACKGROUND: Despite the initial success of high-dose therapy and bone marrow transplant, the major reason for posttransplant failure is relapse of disease. Reinfusion of tumor cells may contribute to relapse in autologous stem cell transplants. We now have ultra-sensitive methods of tumor cell detection that can determine the presence of minimal residual cancer (MRC) in marrow and peripheral blood stem cells. METHODS: The author has conducted a critical review of the literature on this issue. Results: The factors that are associated with an increase in contamination of the graft include (1) the number of cycles of induction therapy, (2) the type of mobilization regimen used, (3) the presence of tumor cells in the marrow, and (4) the number of phereses. A number of studies show that the presence of occult breast cancer in the marrow and/or stem cell product predicts for a poor posttransplant clinical outcome. The presence of clonogenic breast cancer or lymphoma cells in the graft is also associated with a very poor outcome. Published data regarding contamination in graft and outcome for patients with myeloma are limited. CONCLUSIONS: Testing for minimal MRC in the oncology patient provides prognostic information that may be useful to the transplant physician.

Journal Article↗
PubMed2000

Chromosomal abnormalities in women with breast cancer after autologous stem cell transplantation are infrequent and may not predict development of therapy-related leukemia or myelodysplastic syndrome.

We determined prospectively the incidence of chromosomal abnormalities in patients with high-risk breast cancer (HRBC) after high-dose chemotherapy (HDCT) and autologous stem cell transplantation (ASCT), and correlated the cytogenetic abnormalities with the development of post-transplant myelodysplastic syndrome or acute myeloid leukemia (MDS/AML). From 1990 to 1999, 229 women with HRBC underwent ASCT. Cytogenetic analysis of bone marrow (BM) cells was performed 12-59 months after ASCT in 60 consecutive women uniformly treated with six courses of FAC/FEC followed by HDCT and ASCT. With a median follow-up of 36 months after ASCT, there were no cases of MDS/AML among the 229 patients. In the selected cohort of 60 patients, three (5%) showed clonal chromosomal abnormalities (two single trisomy X and one t(1;6)), whereas two additional patients showed non-clonal reciprocal translocations. Two of the patients with clonal aberrations had blood cytopenias as well as subtle dysplastic pictures in BM which were not classifiable as MDS according to the FAB criteria. Similar dysplastic features were also observed in four patients with normal karyotypes. All cytogenetic aberrations were transient and disappeared, except a +X detected by FISH in a residual cell population in one of the patients. Retrospective cytogenetic and FISH studies of samples obtained after six cycles of FAC/FEC and before transplant demonstrated no chromosomal abnormalities in any of the five patients with post-ASCT karyotypic changes. Early changes in karyotype detected in breast cancer patients following ASCT are transient and do not correlate with or predict development of MDS/AML. As these aberrations were not present before ASCT, they may be related to the HDCT regimen or transplant procedure rather than to the prior adjuvant therapy. Our results suggest that ASCT may be less likely to cause MDS or AML in breast cancer patients as compared to other malignancies. Bone Marrow Transplantation (2000) 25, 1203-1208.

Adult↗
PubMed2002

Breast cancer cell contamination of blood stem cell products in patients with metastatic breast cancer: predictors and clinical relevance.

The incidence and clinical relevance of tumor cells contaminating the stem cell products of patients with advanced breast cancer treated with high-dose chemotherapy is uncertain because prior studies used small sample sizes and lacked standardization of the immunocytochemistry (ICC) detection method used. We evaluated blood stem cell and bone marrow samples obtained from 535 women with metastatic breast cancer who received high-dose chemotherapy and unmanipulated mobilized blood stem cell support. Of the patients tested, 20.6% and 26.3% had blood stem cell and bone marrow contamination, respectively. Blood stem cell contamination was significantly more frequent in patients with marrow involvement than in patients without marrow involvement (35% versus 18.4%, respectively; P = .009). In fact, according to multivariate analysis results, marrow involvement was the only significant predictor for blood stem cell product contamination. Patients without marrow involvement who had fewer apheresis procedures were also observed to have a significantly lower incidence rate of blood stem cell contamination than patients who had more procedures (P < or = .008), and patients who received combined chemotherapy and cytokine mobilization therapy had less contamination than patients who received cytokine alone (P = .0001). Combined mobilization therapy appears to be associated with a lower incidence of contamination as a result of fewer apheresis procedures rather than through an antitumor effect of chemotherapy (P < or = .001). Patients with ICC-negative blood stem cell products had significantly longer progression-free survival (PFS) and overall survival (OS) than did patients with ICC-positive blood stem cell products (median PFS, 401 versus 291 days, respectively, P = .007; median OS, 1060 versus 697 days, P = .009) . However, multivariate analysis did not reveal any significant independent predictors of survival outcomes. Thus, further study is needed to determine if contaminating tumor cells in the stem cell products of breast cancer patients ever directly impact survival outcomes or are only indicative of residual in vivo disease in high-dose chemotherapy recipients.

Adult↗
PubMed1989

Isolation and storage of peripheral blood hematopoietic stem cells for autotransplantation into children with cancer.

Peripheral blood stem cells (PBSC) were collected for autotransplantation by a total of 46 continuous-flow leukaphereses in 17 children with various types of cancer in whom the stem-cell pool had been expanded by chemotherapy. As the cells collected by leukapheresis were contaminated with many visible cell clumps, platelets, and erythrocytes, they were separated from the platelet-rich plasma (PRP) by slow-speed centrifugation and fractionated on a discontinuous gradient of Percoll. All the hematopoietic progenitors (CFU-GM, CFU-GEMM) in the starting samples were recovered at the interface of 40% and 60% Percoll solutions largely free of other cellular components and with a substantial reduction in volume. The separation and freezing procedures could be completed within three hours after obtaining cells by leukapheresis. After their fractionation and storage, these PBSC were shown to be able to reconstitute normal hematopoiesis in ten children with poor prognosis leukemia or neuroblastoma for whom no HLA-compatible marrow donors were available and who had been subjected to marrow-ablative therapy. This separation procedure is simple, efficient, and readily available and can be used for children as a routine procedure for PBSC autotransplantation.

Adolescent↗
PubMed1999

Tumour cell detection in G-CSF mobilised stem cell harvests of patients with breast cancer.

Peripheral blood stem cells were mobilised with G-CSF from steady-state haemopoiesis after previous anthracyclin-containing standard dose chemotherapy in patients with high-risk breast cancer. 48 samples were obtained from patients with stage II-III breast cancer and > or = 10 lymph nodes, 15 samples from patients with chemotherapy sensitive metastatic disease, and 13 samples from women with inflammatory breast cancer. 44 samples were first or single leukaphereses and 32 samples were second or third harvests. Aliquots were searched for contaminating tumour cells by immunocytochemistry (IC) and cytokeratin-19 reverse transcriptase polymerase chain reaction rtPCR). The median count of MNCs examined by IC was 2 x 10(6); cDNA prepared from 2 x 10(7) cells was subjected to PCR. Fifty-nine samples were examined by immunocytochemistry, 36 samples by rtPCR, and 19 samples by both techniques. Samples investigated by IC and rtPCR were judged as positive if there was at least one positive test. On the whole, 42/79 (55.3%) of the samples were positive with an insignificant trend to a higher positivity rate in second or subsequent leukaphereses (52.3% vs 59.3%). The median tumour cell load per 10(6) MNCs was low with 0.5 (0-7) cells in all, and a total of 2.2 (0.5-7) cells in positive specimen. Differences in the cancer cell load of first and subsequent leukaphereses and between subgroups of patients were not found. PCR and IC gave consistent results in 63.2%. This phenomenon can be explained by the greater sensitivity of the molecular method and by a Poisson distribution of coharvested tumour cells in samples. Tumour cell contamination in G-CSF mobilised stem cells from patients with breast cancer from steady state haemopoiesis after preceding anthacyclin-containing chemotherapy is frequent, but the tumour cell load is low. To allow a comparison of different studies dealing with cancer cell contamination in stem cells, standardisation of assays is necessary.

Breast Neoplasms↗
PubMed2005

Transforming growth factor-beta signaling in stem cells and cancer.

Transforming growth factor-beta (TGF-beta) and TGF-beta-related proteins, such as the bone morphogenetic proteins, have emerged as key regulators of stem cell renewal and differentiation. These proteins have disparate roles in regulating the biology of embryonic stem cells and tumor suppression, and they help define the selection of cell fate and the progression of differentiation along a lineage. Here we illustrate their roles in embryonic stem cells and in the differentiation of neural, hematopoietic, mesenchymal, and gastrointestinal epithelial stem cells.

Animals↗