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PubMed1996

Does an inability to eradicate normal stem cells preclude the cure of some cancers?

Presently, identified signal transduction pathways do not alter normal stem-cell survival. With prostate cancer as a model, the argument is advanced that an inability to eradicate normal androgen-dependent prostate stem-cells precludes successful treatment of transformed, androgen-independent and metastatic progeny. While applying this idea to cancers of non-essential organs or to endocrine cancers seems feasible, the inutility of this approach for most other malignancies appears likely, although not certain.

Animals↗
PubMed2003

Autologous hematopoietic stem cell transplantation for breast cancer in Europe: critical evaluation of data from the European Group for Blood and Marrow Transplantation (EBMT) Registry 1990-1999.

The aim of this study was to identify trends in high-dose chemotherapy (HDC) with autologous hematopoietic stem cell transplantation (ASCT) and to assess survival in a large cohort of breast cancer (BC) patients receiving this therapy in Europe from 1990 to 1999. A total of 7471 patients who received HDC with ASCT between January 1, 1990 and December 31, 1999 were reported to the European Group for Blood and Marrow Transplantation Registry. Data required for demographics and survival analysis were available for 2679 patients with high-risk primary BC; 921 patients with inflammatory BC (IBC), and 2295 patients with metastatic disease. The main evaluation parameters were progression-free survival (PFS) and overall survival (OS). Between 1990 and 1998, autotransplants for BC increased 30-fold. Significant trends included use of blood-derived rather than marrow-derived stem cells, increment of reporting centers and decrease of mortality within 100 days from transplantation. The 5-year PFS and OS probabilities were 53 and 68% for high-risk disease and 42 and 53% for IBC, respectively. For metastatic disease 5-year PFS and OS probabilities in the whole cohort were 18 and 27%, respectively, while for women transplanted in complete remission the 5-year PFS was 29%. In conclusion, HDC with ASCT has been increasingly used until 1998 and the 100-day mortality rate has been constantly less than 2% from 1995 to date. The 5-year survival of high-risk BC is related to the number of axillary nodes involved at surgery. Outcome of patients with IBC is encouraging, suggesting the need for randomized trials. Patients with metastatic disease responding to pretransplant chemotherapy and harboring ER+ tumors have a better outcome.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2005

Role of polycomb group proteins in stem cell self-renewal and cancer.

Polycomb group proteins (PcG) form part of a gene regulatory mechanism that determines cell fate during normal and pathogenic development. The mechanism relies on epigenetic modifications on specific histone tails that are inherited through cell divisions, thus behaving de facto as a cellular memory. This cellular memory governs key events in organismal development as well as contributing to the control of normal cell growth and differentiation. Consequently, the dysregulation of PcG genes, such as Bmi1, Pc2, Cbx7, and EZH2 has been linked with the aberrant proliferation of cancer cells. Furthermore, at least three PcG genes, Bmi1, Rae28, and Mel18, appear to regulate self-renewal of specific stem cell types suggesting a link between the maintenance of cellular homeostasis and tumorigenesis. In this review, we will briefly summarize current views on PcG function and the evidence linking specific PcG proteins with the behavior of stem cells and cancer cells.

Animals↗
PubMed2005

Cloning of the nucleostemin gene and its function in transforming human embryonic bone marrow mesenchymal stem cells into F6 tumor cells.

We recently established a novel tumor cell line denominated as F6, which was derived from mutated human embryonic bone marrow mesenchymal stem cells (MSCs). The difference between gene expression of F6 cells and MSCs was distinguished by fluorescent differential display. Results showed that the expression of nucleostemin, a novel factor participating in the control of stem and cancer cell proliferation, was different in F6 cells and MSCs. To further understand its role in transforming human embryonic bone marrow mesenchymal stem cells into F6 tumor cells, the full-length nucleostemin gene (1650 bp) from an LTEP-a-2 cell line was cloned, and GST-nucleostemin protein was expressed in E. coli. The characteristics of nucleostemin expression in F6 cells and other human cancer cell lines were investigated by RT-PCR, Western blot analysis, immunocytochemical staining, fluorescent microscope and confocal laser scanning microscope. The levels of nucleostemin gene expression were detected by real-time PCR in F6 tumor tissue obtained from SCID nude mice at 4, 6 and 7 weeks after the injection of F6 cells, and from the lung tissue of five lung cancer patients. Results showed that nucleostemin gene expression increased significantly in F6 tumor tissue and lung cancer tissue. The results also showed that transfection with pcDNA3.1(+)-GFP-nucleostemin for 4-20 weeks promoted cell size augmentation and nuclei multiplication, and the cells were converted to giant cell-like cells. Western blot analysis revealed that expression levels of nucleostemin in the nuclei and cytoplasm of cancer cell lines, e.g. F6, LTEP-a-2, U937, SW480 and 95D, were higher than those in MSCs and COS-7 cells. Levels of nucleostemin in F6 cells were notably high and confirmed with immunohistochemical staining. These results implied that nucleostemin may play an important role in both tumorigenesis and transforming human embryonic bone marrow mesenchymal stem cells into F6 tumor cells.

Animals↗
PubMed1980

Feedback in cancer.

The theory presented regards cancer as a systemic disease initiated by carcinogens, and neoplasia as the organism's main defence against it. Carcinogens are assumed to destroy a vital substance "A" which is replenished by a second, "B", produced by neoplastic stem cells. Cancer progression is manifested by a gradual deterioration of the "A" producing machinery accompanied by a compensatory proliferation of neoplastic "B" producing stem cells whose size is therefore closely regulated so as to meet the organism's demands. Any stem cell pool reduction leading to a loss of "A" or "B" is followed by a proliferation of the remaining stem cells to replenish the loss. Such may be observed in chronic lymphoblastic leukemia maintaining a nearly constant elevated peripheral lymphoblast count. Following selective lymphoblast destruction the count is rapidly replenished to its pretreatment level. The same mechanism is assumed to explain the detrimental effect of some surgical interventions on cancer patients. Neoplastic progression is postulated to a obey a "stem cell conservation" principle which when violated is followed either by a stem cell replenishment or aggrevates the patient's conditions. This conservation law introduces a new definition of carcinogenesis: Any process reducing the "A" or "B" producing machinery is regarded as a carcinogen. A definition embracing, surgical extirpation of normal or neoplastic stem cells or cell destruction by irradiation, chemotherapy or chemical carcinogens.

Carcinogens↗
PubMed2003

Stem-cell hierarchy in skin cancer.

Tumour architecture mimics many of the features of normal tissues, with a cellular hierarchy that regulates the balance between cell renewal and cell death. Although many tumours contain cells with the characteristics of stem cells, the identity of the normal cells that acquire the first genetic hits leading to initiation of carcinogenesis has remained elusive. Identification of the primary cell of origin of cancers and the mechanisms that influence cell-fate decisions will be crucial for the development of novel non-toxic therapies that influence tumour-cell behaviour.

Animals↗
PubMed2005

Microarray analysis identifies a death-from-cancer signature predicting therapy failure in patients with multiple types of cancer.

Activation in transformed cells of normal stem cells' self-renewal pathways might contribute to the survival life cycle of cancer stem cells and promote tumor progression. The BMI-1 oncogene-driven gene expression pathway is essential for the self-renewal of hematopoietic and neural stem cells. We applied a mouse/human comparative translational genomics approach to identify an 11-gene signature that consistently displays a stem cell-resembling expression profile in distant metastatic lesions as revealed by the analysis of metastases and primary tumors from a transgenic mouse model of prostate cancer and cancer patients. To further validate these results, we examined the prognostic power of the 11-gene signature in several independent therapy-outcome sets of clinical samples obtained from 1,153 cancer patients diagnosed with 11 different types of cancer, including 5 epithelial malignancies (prostate, breast, lung, ovarian, and bladder cancers) and 5 nonepithelial malignancies (lymphoma, mesothelioma, medulloblastoma, glioma, and acute myeloid leukemia). Kaplan-Meier analysis demonstrated that a stem cell-like expression profile of the 11-gene signature in primary tumors is a consistent powerful predictor of a short interval to disease recurrence, distant metastasis, and death after therapy in cancer patients diagnosed with 11 distinct types of cancer. These data suggest the presence of a conserved BMI-1-driven pathway, which is similarly engaged in both normal stem cells and a highly malignant subset of human cancers diagnosed in a wide range of organs and uniformly exhibiting a marked propensity toward metastatic dissemination as well as a high probability of unfavorable therapy outcome.

Animals↗
PubMed2000

Pulmonary function and complications following chemotherapy and stem cell support in breast cancer.

Pulmonary complications are frequent in patients treated with high-dose chemotherapy and autologous bone marrow transplantation for breast cancer or other solid tumours. This study analyses the development of lung toxicity, changes in respiratory function and occurrence of clinical symptoms in a group of 24 patients (mean age 46+/-7 yrs) who underwent high-dose sequential chemotherapy (HDS) with autologous peripheral blood stem cell (PBSC) support for high risk breast cancer. Clinical examination, chest radiography and lung function tests were performed before the HDS and 1 and 3 months following transplantation. Only one patient developed acute interstitial pulmonary disease which resolved after prednisone therapy. No patients developed infectious complications after transplantation. Baseline respiratory function was normal for most of the parameters. Only lung diffusing capacity of the lung for carbon monoxide (TL,CO) and maximal inspiratory pressure were below the normal range. Following PBSC transplantation only one patient had an altered vital capacity while 72.3% of patients had reduced TL,CO values at 1 month and 54.5% at 3 months after transplantation. Maximal expiratory flow at 25% forced vital capacity, TL,CO and maximal expiratory pres-sure were significantly reduced after 1 month but recovered slightly by 3 months. Arterial oxygen tension between baseline and both follow-up evaluations declined significantly in patients seropositive for human cytomegalovirus. It is concluded that this high-dose sequential chemotherapy regimen is acceptably safe since no pulmonary related mortality or respiratory infectious complications were observed. The only lung function alteration induced was an isolated diffusing capacity of the lung for carbon monoxide impairment, clinically negligible and partially recovered within 3 months.

Adult↗
PubMed2006

Parental desire and acceptability of spermatogonial stem cell cryopreservation in boys with cancer.

BACKGROUND: In the near future, a substantial proportion of adults will be childhood cancer survivors. The cryopreservation and transplantation of spermatogonial stem cells (SSCs) is currently successful in animals; application in humans seems likely in the near future. Cryopreserving SSCs might become an important issue in childhood cancer. Because this might require testicular biopsies or hemicastration, parental desire/acceptability for SSC collection was enquired for. METHODS: Three hundred eighteen parents of boys surviving at least 2 years after the diagnosis of cancer were asked about collecting SSCs by biopsy or hemicastration and collecting sperm by masturbation or electrostimulation. Opinions were assessed as if at the time of diagnosis and at the present time. RESULTS: Sixty-three per cent of parents responded. At diagnosis, SSC collection by means of biopsy was approved by 61%, hemicastration by 33% and collecting sperm by 70% (P < 0.013). The acceptability of performing hemicastration was significantly lower than all other forms of SSC/sperm collection. No differences were observed between parents' present opinion and opinion at diagnosis. No differences related to treatment intensity, presumed negative fertility effects and pubertal state were found. CONCLUSIONS: Infertility is a major topic for parents. For prepubertal boys, the collection of SSCs might be a great relief in respect of the fertility issue. Collecting SSCs by biopsy is desired and accepted by the majority of parents; hemicastration is accepted by one-third of parents. The translation of SSC cryopreservation and transplantation from animal models to humans is eagerly awaited.

Adolescent↗
PubMed2006

Neurologic complications of bone marrow, stem cell, and organ transplantation in patients with cancer.

Bone marrow and peripheral blood stem cell transplantation are part of the standard of care for a variety of oncologic and non-oncologic disorders and are associated with a large spectrum of neurologic complications. These complications may arise at any time during and after the transplantation process, especially in subjects requiring chronic immunosuppression, and are most frequently related to infections, cerebrovascular or metabolic events, and toxicity from radiation or chemotherapy. Due to the unique circumstances and treatments surrounding each step in the transplantation process, there is a higher incidence of some neurologic complications during discrete time periods. Being aware of the temporal relationship of the neurologic disorder within the transplantation process can therefore facilitate diagnosis and institution of appropriate therapy. Neurologic complications after solid organ transplantation are often due to similar mechanisms as in patients after bone marrow and stem cell transplantation although there are several complications unique to these patients such as transmission of infectious agents by the donated organ. For these patients, the clinician needs to have a high index of suspicion that the neurologic problem is related to the transplant.

Bone Marrow Transplantation↗
PubMed2001

Infectious complications in breast cancer patients undergoing peripheral blood stem cell transplantation: a single center retrospective analysis towards outpatient strategy.

Infectious complications were retrospectively analyzed in 129 transplants, performed in 90 patients, to identify characteristics that qualify breast cancer patients for outpatient-based PBSCT. Thirty-one cases (24%) did not develop fever. Of the remaining 98 cases, 84.7% developed fever during severe neutropenia. On univariate analysis, disease stages II-III, first PBSCT, mucositis grades II-IV and the use of two alkylators were associated with a higher risk of fever development. The latter two factors also affected fever occurrence on multivariate analysis. A longer median time to fever onset was observed in patients conditioned with single as compared to double alkylating agent-containing regimens (respectively 8th vs 6th day, P < 0.00001). As compared with metastatic breast cancer (MBC), high risk breast cancer showed a 2.3-fold increased risk of developing early fever during neutropenia (CI 2.3-3.8), remaining the only variable still significant on multivariate analysis (P = 0.0039). Combination antibiotic therapy was equivalent to single agent therapy. Patients suffering from microbiologically documented fever were at higher risk of undergoing second-line antibiotic therapy. In conclusion, MBC patients treated with a conditioning regimen containing only one alkylating agent and adequate prophylaxis for mucositis may qualify for outpatient-based PBSCT on the basis of a lower risk of infection.

Adult↗
PubMed1993

DNA lesions, inducible DNA repair, and cell division: three key factors in mutagenesis and carcinogenesis.

DNA lesions that escape repair have a certain probability of giving rise to mutations when the cell divides. Endogenous DNA damage is high: 10(6) oxidative lesions are present per rat cell. An exogenous mutagen produces an increment in lesions over the background rate of endogenous lesions. The effectiveness of a particular lesion depends on whether it is excised by a DNA repair system and the probability that it gives rise to a mutation when the cell divides. When the cell divides, an unrepaired DNA lesion has a certain probability of giving rise to a mutation. Thus, an important factor in the mutagenic effect of an exogenous agent whether it is genotoxic or non-genotoxic, is the increment it causes over the background cell division rate (mitogenesis) in cells that appear to matter most in cancer, the stem cells, which are not on their way to being discarded. Increasing their cell division rate increases mutation and therefore cancer. There is little cancer from nondividing cells. Endogenous cell division rates can be influenced by hormone levels, decreased by calorie restriction, or increased by high doses of chemicals. If both the rate of DNA lesions and cell division are increased, then there will be a multiplicative effect on mutagenesis (and carcinogenesis), for example, by high doses of a mutagen that also increases mitogenesis through cell killing. The defense system against reactive electrophilic mutagens, such as the glutathione transferases, are also almost all inducible and buffer cells against increments in active forms of chemicals that can cause DNA lesions. A variety of DNA repair defense systems, almost all inducible, buffer the cell against any increment in DNA lesions. Therefore, the effect of a particular chemical insult depends on the level of each defense, which in turn depends on the past history of exposure. Exogenous agents can influence the induction and effectiveness of these defenses. Defenses can be partially disabled by lack of particular micronutrients in the diet (e.g., antioxidants).

Animals↗
PubMed2005

The function of breast cancer resistance protein in epithelial barriers, stem cells and milk secretion of drugs and xenotoxins.

The breast cancer resistance protein [BCRP (also known as ABCG2)] belongs to the ATP binding cassette (ABC) family of transmembrane drug transporters. BCRP has a broad substrate specificity and actively extrudes a wide variety of drugs, carcinogens and dietary toxins from cells. Situated in the apical plasma membrane of epithelial cells of the small and large intestine and renal proximal tubules and in the bile canalicular membrane of hepatocytes, BCRP decreases the oral availability and systemic exposure of its substrates. In several blood-tissue barriers BCRP reduces tissue penetration of its substrates and it protects haematopoietic stem cells from cytotoxic substrates. Moreover, BCRP is expressed in mammary gland alveolar epithelial cells during pregnancy and lactation, where it actively secretes a variety of drugs, toxins and carcinogens into milk. In apparent contradiction with the detoxifying role of BCRP in mothers, this contamination of milk exposes suckling infants and dairy consumers to xenotoxins. BCRP thus affects many important aspects of pharmacology and toxicology.

ATP Binding Cassette Transporter, Subfamily G, Mem↗
PubMed1999

Gene therapy of genetic diseases and cancer.

The scope of gene transfer applications in human therapy has expanded enormously over the last 15 years to include not only several types of genetic diseases but also a variety of genetic approaches to the treatment of cancer. Hematopoietic stem cells have been considered excellent targets for therapeutic gene transfer because of their capacity for self-renewal and for differentiation into multiple cellular lineages. Retrovirus-mediated gene transfer has been tested for treatment of diseases that specifically affect the hematopoietic system, such as adenosine deaminase deficiency and chronic granulomatous disease. Storage disorders such as Gaucher disease, Hurler syndrome and Hunter syndrome, genetic deficiencies that affect a broad range of tissue types, may also be amenable to treatment by gene transfer into hematopoietic cells, owing to the release of enzyme expressed in transduced cells with subsequent uptake by untransduced cells ("metabolic cross-correction"). Hematopoietic stem cells may also be targeted for introduction of drug-resistance genes for the purpose of protecting normal tissues from the toxic side-effects of cancer chemotherapeutic agents, thus allowing more effective antitumor chemotherapy. The danger of introducing drug-resistance function into tumor cells may be dealt with by including sequences specifically designed to reduce expression of oncogenes or to restore expression of tumor suppressor genes. Current limitations on the efficiency of gene transfer into hematopoietic stem cells may be alleviated by the development of new vector systems such as adeno-associated virus or lentivirus vectors, or by advances in cell processing that render hematopoietic cells more susceptible to transduction. Drug-resistance genes may also be applied for in vivo selection to expand the representation of a small proportion of transduced hematopoietic cells. These approaches toward increasing the frequency of hematopoietic cell transduction contribute to the anticipated feasibility of gene therapy for genetic diseases and cancer.

Child↗
PubMed2001

Residual tumor cell contamination in peripheral blood stem cells collections of 117 breast cancer patients evaluated by immunocytochemical technique.

During the last years, high-dose chemotherapy and hematopoietic stem cell support have been thought to improve the treatment of poor-prognosis breast cancer. Nevertheless, the question remained as to whether the reinfusion of contaminating residual malignant cells could contribute to relapse. By using an immunocytochemical method, we have analyzed the tumor cell contamination of peripheral blood stem cells (PBSC) collected from advanced breast cancer patients. We studied 153 PBSC samples from 117 stage III and IV breast cancer patients and compared two screening methods-the usual microscopic observation and the automated cellular image analysis system (ACIS-assisted) screening. With manual observation, we found that 7 of 117 patients (5.9%) presented circulating epithelial tumor cells in 9 of 153 (5.8%) PBSC analyzed, whereas automated screening allowed positive detection in 15 of the same 117 patients (12.8%) and in 18 of the 153 PBSC (11.7%). No difference was found between presence or absence of circulating tumor cells and previous chemotherapy treatment (p = 0.5) or stage TNM (p = 0.13) in this group of poor-prognosis breast cancer. We did not find incidence of infusion of contaminated PBSC on overall survival or time to progression.

Adult↗
PubMed1998

[Mobilization of peripheral blood stem cells in advanced ovarian cancer].

High-dose chemotherapy with hematopoietic support has been expected to improve the survival of advanced ovarian cancer patients in recent years. An essential component of such treatment has been the ability to collect and reinfuse a large number of peripheral blood stem cells (PBSCs) following high dose therapy. This study was designed to determine which clinical and hematological factors would be better indicators to collect the proper volume of PBSCs. Thirteen patients received a total of 24 courses of induction chemotherapy and 69 of apheresis. We usually mobilized stem cells using CEP chemotherapy (cisplatin 50-70 mg/m2, epirubicin 50 mg/m2 and cyclophosphamide 1.5 g/m2) with G-CSF and CEE regimen (cyclophosphamide 2.0 g/m2, epirubicin 50 mg/m2, and etoposide 50 mg/m2) as a salvage for mobilization. We obtained an average 5 x 10(6)/kg of CD34+ cells for 3 days as one course. The number of CD34+ cells collected significantly depended on the platelets and reticulocytes on the first day of apheresis, but not a nadir of WBCs. It is concluded that apheresis should be started on recovery of WBCs to 5,000-10,000/microliters, of immature granulocytes to > or = 10% and of reticulocytes to > or = 20%. This study confirmed the feasibility of collecting enough PBSCs to use standard chemotherapy of ovarian cancer patients.

Adult↗
PubMed1997

Increased frequency of autoaggression syndrome associated with autologous stem cell transplantation in breast cancer patients.

In our BMT Unit, we have observed a high frequency of skin rash associated with fever and other clinical findings during engraftment of autologous BM and/or PBSC. Thirty patients with breast cancer and 12 patients with Hodgkin's or non-Hodgkin's lymphoma, treated with the same regimen, were analyzed retrospectively or prospectively to characterize the clinical syndrome, its frequency, and its clinical course, as well as to define the factors affecting its incidence. In patients developing skin rash, the median and range for time to onset of skin rash and for time to increase in WBC after reinfusion of stem cells were identical (8 days, range 5-13) and did not differ significantly (P = 0.533). Twenty-three patients (55%) had skin rash, 18 patients had fever. Other, less frequent manifestations include platelet transfusion refractoriness (PTR), diarrhea, diffuse alveolar hemorrhage, and autoimmune thrombocytopenia or hemolytic anemia. A higher proportion of breast cancer patients developed the syndrome in comparison to lymphoma patients (67% vs 25%, P = 0.051). Acute GVHD grade I-II was established histologically in six patients with the syndrome. Comparison of the incidence of the syndrome by different variables using Fisher's exact test revealed significance for disease category (P = 0.02) and number of previous treatment regimens (P = 0.002) as predictive factors for developing the autoaggression syndrome. In other words, patients with breast cancer and those with only one previous treatment regimen were more likely to develop the syndrome. This study suggests that an autoaggression GVHD-like syndrome accompanies the early phase of autologous engraftment and that a higher frequency of the syndrome might be seen in breast cancer patients undergoing high-dose chemotherapy and autologous stem cell transplantation.

Adult↗