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PubMed2006

A WNTer wonderland in Snowbird.

The Keystone Symposium on ;Wnt and beta-catenin signaling in development and disease' was held recently in Snowbird, UT, USA. Organized by Mariann Bienz and Hans Clevers, this meeting covered a wide range of topics, including Wnt protein biogenesis, Wnt receptors and signaling pathways, beta-catenin/Tcf complexes and gene expression, Wnt signaling in development, cancer, stem cell biology and regeneration, and therapeutics that target the Wnt/beta-catenin pathway.

Animals↗
PubMed2007

Gastric and intestinal phenotypic correlation between exocrine and endocrine components in human stomach tumors.

We have previously suggested that an origin of a stomach cancer is from a progenitor cell specializing toward exocrine cell (Exo-cell) lineages. To clarify whether our hypothesis is correct or not, we analyzed the expression of Exo-cell and endocrine cell (End-cell) markers in a series of lesions for comparison. We evaluated chromogranin A (CgA) expression in 37 early and 73 advanced stomach cancers, in 30 stomach adenomas, in 8 carcinoid tumors, and in 4 endocrine cell carcinomas (ECCs) with assessment of gastric and/or intestinal (G/I) phenotypes in both Exo-cell and End-cell by immunohistochemistry. CgA expression was observed in 10.8% of the early and 16.4% of the advanced stomach cancers, respectively. The End-cell G/I phenotypes were in line with the Exo-cell counterparts in the CgA-positive stomach cancerous areas, and there was strong association between Cdx2 expression and the intestinal End-cell markers. All of the adenoma cases had the intestinal Exo-cell phenotypic expression, with the positive link between Exo-cell and End-cell G/I phenotypes. All stomach carcinoids had CgA expression but no expression of Exo-cell markers. In conclusion, most stomach cancers might develop from a progenitor cell specializing towards Exo-cell lineages, but some cases possessed both Exo-cell and End-cell markers with maturely differentiated phenotypes. In such cases, Exo-cell and End-cell phenotypes were found to correlate strongly, suggesting the possibility of histogenesis from "cancer stem cells".

Adenocarcinoma↗
PubMed2006

Significance, detection and markers of disseminated breast cancer cells.

The development of distant metastases is the major cause of death from breast cancer. In order to predict and prevent tumour spreading, many attempts are being made to detect small numbers of tumour cells that have shed from the primary lesions and have moved to lymph nodes, blood or bone marrow. This article presents the advantages and the limitations of techniques used for disseminated tumour cells (DTC) detection. DTC markers are listed and the most currently used of them (KRT19, CEACAM5, TACSTD1, MUC1, EGFR, ERBB2, SCGB2A2, SCGB2A1, SCGB1D2, PIP, SBEM, TFF1, TFF3, ANKRD30A, SPDEF, ESR1, SERPINB5 and GABRP) are discussed, notably on the basis of recent data on breast tumour portraits (luminal epithelial-like, basal/myoepithelial-like and ERBB2). The significance of DTC for the prognosis and prediction of response to therapy is examined. DTC viability, the notion of cell dormancy and the concept of breast cancer stem cells are also discussed.

Antigens, Neoplasm↗
PubMed2005

Molecular cytogenetic analysis in the study of brain tumors: findings and applications.

Classic cytogenetics has evolved from black and white to technicolor images of chromosomes as a result of advances in fluorescence in situ hybridization (FISH) techniques, and is now called molecular cytogenetics. Improvements in the quality and diversity of probes suitable for FISH, coupled with advances in computerized image analysis, now permit the genome or tissue of interest to be analyzed in detail on a glass slide. It is evident that the growing list of options for cytogenetic analysis has improved the understanding of chromosomal changes in disease initiation, progression, and response to treatment. The contributions of classic and molecular cytogenetics to the study of brain tumors have provided scientists and clinicians alike with new avenues for investigation. In this review the authors summarize the contributions of molecular cytogenetics to the study of brain tumors, encompassing the findings of classic cytogenetics, interphase- and metaphase-based FISH studies, spectral karyotyping, and metaphase- and array-based comparative genomic hybridization. In addition, this review also details the role of molecular cytogenetic techniques in other aspects of understanding the pathogenesis of brain tumors, including xenograft, cancer stem cell, and telomere length studies.

Animals↗
PubMed2004

Neosis: a novel type of cell division in cancer.

Using computerized video time-lapse microscopy, we studied early cellular events during carcinogen-induced transformation of C3H10T1/2 cells. Multinucleate/polyploid giant cells (MN/PGs) formed due to DNA damage are thought to die via mitotic catastrophe. Before they die, some MN/PGs undergo a novel type of cell division, termed neosis, characterized by karyokinesis via nuclear budding followed by asymmetric, intracellular cytokinesis, producing several small mononuclear cells, termed the Raju cells, with extended mitotic life span (MLS). Mitotic derivatives of Raju cells give rise to transformed cell lines, inherit genomic instability, display a phenotype and transcriptome different from the neosis mother cell, and anchorage-independent growth. Neosis of MN/PGs also precedes spontaneous transformation of p53-/- mouse cells. Rodent neotic clones, and primary and metastatic human tumor cells undergo spontaneous or induced secondary/tertiary neosis. Neosis seems to extend the MLS of cells under conditions of genetic duress not favoring mitosis. It precedes tumorigenesis, occurs several times during tumor progression, yielding tumor-initiating Raju cells and introducing tumor cell heterogeneity subject to natural selection during tumor progression. Events during neosis, and its relevance to origin of established cell lines, multistep carcinogenesis, cancer stem cells, and therapeutic advantages of anti-neotic agents (neosicides) are discussed.

Animals↗
PubMed2006

Cross-talk of WNT and FGF signaling pathways at GSK3beta to regulate beta-catenin and SNAIL signaling cascades.

WNT and FGF signaling pathways cross-talk during a variety of cellular processes, such as human colorectal carcinogenesis, mouse mammary tumor virus (MMTV)-induced carcinogenesis, E2A-Pbx-induced leukemogenesis, early embryogenesis, body-axis formation, limb-bud formation, and neurogenesis. Canonical WNT signals are transduced through Frizzled receptor and LRP5/6 coreceptor to downregulate GSK3beta (GSK3B) activity not depending on Ser 9 phosphorylation. FGF signals are transduced through FGF receptor to the FRS2-GRB2-GAB1-PI3K-AKT signaling cascade to downregulate GSK3beta activity depending on Ser 9 phosphorylation. Because GSK3beta-dependent phosphorylation of beta-catenin and SNAIL leads to FBXW1 (betaTRCP)-mediated ubiquitination and degradation, GSK3beta downregulation results in the stabilization and the nuclear accumulation of beta-catenin and SNAIL. Nuclear beta-catenin is complexed with TCF/LEF, Legless (BCL9 or BCL9L) and PYGO (PYGO1 or PYGO2) to activate transcription of CCND1, MYC, FGF18 and FGF20 genes for the cell-fate determination. Nuclear SNAIL represses transcription of CDH1 gene, encoding E-cadherin, to induce the epithelial-mesenchymal transition (EMT). Mammary carcinogenesis in MMTV-Wnt1 transgenic mice is accelerated by MMTV infection due to MMTV integration around Fgf3-Fgf4 or Fgf8 loci, and mammary carcinogenesis in MMTV-Fgf3 transgenic mice due to MMTV integration around Wnt1-Wnt10b locus. Coactivation of WNT and FGF signaling pathways in tumors leads to more malignant phenotypes. Single nucleotide polymorphism (SNP) and copy number polymorphism (CNP) of WNT and FGF signaling molecules could be utilized as screening method of cancer predisposition. cDNA-PCR, microarray or ELISA reflecting aberrant activation of WNT and FGF signaling pathways could be developed as novel cancer-related biomarkers for diagnosis, prognosis, and therapy. Cocktail therapy using WNT and FGF inhibitors, such as small-molecule compounds and human neutralizing antibodies, should be developed to increase the efficacy of chemotherapy through the inhibition of recurrence by destructing cancer stem cells.

Animals↗
PubMed2006

Usefulness of predictive tests for cancer treatment.

This review highlights the numerous molecular biology findings in the field of lung cancer with potential therapeutic impact in both the near and distant future. At least six lines of research have recently emerged as potential contributors to changes in clinical practice. Abundant pre-clinical and clinical data indicate that BRCA1 mRNA expression is a differential modulator of chemotherapy sensitivity. Low levels predict cisplatin sensitivity and antimicrotubule drug resistance, and the opposite occurs with high levels. Secondly, single nucleotide polymorphisms in the ERCC1 gene influence survival and toxicity with cisplatin-based chemotherapy. The main core of recent research has centered on EGFR mutations and gene copy numbers. For the first time, EGFR mutations have been shown to predict dramatic responses in metastatic lung adenocarcinomas, with a threefold increase in time to progression and survival in patients receiving EGFR tyrosine kinase inhibitors. In contrast, K-ras mutations confer a negative effect in these patients. Evidence has also been accumulated on the crosstalk between estrogen and EGFR receptor pathways, paving the way for clinical trials of EGFR tyrosine kinase inhibitors plus aromatase inhibitors. microRNAs control the expression of cognate target genes, and downregulation of Dicer has been shown to be a strong predictor of relapse in surgically resected non-small-cell lung cancer patients. Finally, overexpression of the Wingless-type (Wnt) genes and methylation of Wnt antagonists like WIF and secreted frizzled related proteins have been documented in non-small-cell lung cancer and are believed to be an important mechanism of cancer stem cell maintenance.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1991

Detection and diagnosis of the primary tumor in lung cancer.

The role of radiology in the initial detection and diagnosis of primary lung cancer is well established. Recent advances in the detection of lung cancer stem from research into the visual search patterns used by a radiologist when reading a chest radiograph. Computer feedback of "visual-dwell" positions can lead to an increase in true-positive detection of lung nodules and decrease the false-positive rate. Plain film radiography and CT continue as the mainstays for the characterization of lung nodules. New studies involving the use of conventional tomography to detect contrast enhancement of malignant lesions and the use of axial multiplanar reconstruction CT to demonstrate involvement of pulmonary veins by malignant lesions are detailed. Transbronchial and percutaneous transthoracic biopsy techniques are widely used to diagnose the nature of solitary pulmonary nodules. The dependent positioning of the biopsy site has been shown to decrease both the pneumothorax rate and the frequency of chest drain insertion, whereas the blood patch technique was shown not to affect the pneumothorax rate at all.

Diagnostic Imaging↗
PubMed1987

[Hyaluronidase in the therapy of malignant diseases].

260 patients with malignant disease received intravenous, intramuscular or intravesical hyaluronidase (H.) (Permease by Sanabo), 7,000 to 25,500 IU (10 to 30, 750 IU vials) or 200,000 IU (1 vial of H.) in addition to systemic or intravesical chemotherapy. Treatment was well tolerated except for 20 transient allergic episodes, 2 of which consisted in local symptoms at the injection site. Results are presented for 103 patients not responding to previous chemotherapy, 53 patients with primary and secondary brain tumours, and 51 patients with superficial bladder cancer. Adjuvant hyaluronidase was found to restore responsiveness in a large percentage of non-responders. The remaining systemically treated patients received H. together with their initial chemotherapy or with a modified cytostatic regimen. Intravesical H. in combination with mitomycin C was well tolerated and did not enhance mitomycin C plasma levels. In a randomized trial 5 of 23 patients with superficial bladder cancer receiving adjuvant intravesical mitomycin C alone developed tumour regrowth versus 1 of 21 patients receiving additional H. Adjuvant H. decreased 5-FU plasma saturation rates during arterial perfusion in colorectal cancer with metastatic spread to the liver, probably reflecting enhanced 5-FU extraction. Colorectal cancer stem cell assays with 5-FU showed a significant reduction of colony counts in the presence of H. Action mechanismus of hyaluronidase in malignant diseases are discussed, experimental data suggesting an effect of H. on immunologic events in malignant disease are presented.

Antineoplastic Agents↗
PubMed2004

Predictors of viridans streptococcal shock syndrome in bacteremic children with cancer and stem-cell transplant recipients.

PURPOSE: To describe episodes of viridans streptococcal bacteremia (VSB) in a cohort of children with cancer and stem-cell transplant (SCT) recipients and to determine predictors of viridans streptococcal shock syndrome (VSSS) in this group of children. PATIENTS AND METHODS: For this retrospective review, we included episodes of VSB isolated between March 1997 and September 2002, in children (<or= 18 years) with a diagnosis of cancer or SCT patients. The primary outcome was VSSS, defined as hypotension requiring intravascular volume expansion or inotropic support and/or respiratory insufficiency necessitating assisted ventilation. RESULTS: Eighty-eight episodes of VSB occurred in 79 children. The mean age of the children was 6.7 years (range, 0.6 to 18.0 years). The most common underlying diagnosis was acute myelogenous leukemia (AML) in 31 (35%) of 88 episodes, and 38 (43%) of 88 had undergone SCT. VSSS occurred in 16 (18%) of 88 episodes, and two children died from VSSS. Two variables were predictive of VSSS, namely peak temperature at presentation (odds ratio [OR], 6.3; 95% CI, 2.1 to 19.0; P =.001) and inpatient status (OR, 5.9; 95% CI, 1.3 to 28.0; P =.02). Diagnosis of AML (OR, 1.1; 95% CI, 0.4 to 3.5; P =.8), receipt of SCT (OR, 1.9; 95% CI, 0.6 to 5.7; P =.2), high-dose cytarabine (OR, 0.6; 95% CI, 0.1 to 3.2; P =.6), and mucositis (OR, 0.8; 95% CI, 0.3 to 2.6; P =.7) were not predictive of VSSS. CONCLUSION: VSSS occurred in 18% of episodes of VSB in children with cancer or SCT recipients. Peak temperature before antibiotic therapy and inpatient status were predictive of VSSS.

Adolescent↗
PubMed1996

[High-dose therapy with autologous stem cell support in malignant lymphoma and breast cancer. Experiences with hematopoietic stem cells isolate from blood].

Since 1994, 17 breast cancer patients and 16 lymphoma patients have been treated at the Norwegian Radium Hospital with high-dose therapy supported by autologous peripheral progenitor cells. All the patients were given granulocyte colony stimulating factor in the recovery phase after cytotoxic treatment in order to mobilize and harvest peripheral progenitor cells. Aphareses were successful in all patients and the mean number of CD34 cells reinfused per kilo body weight was 7.05 x 10(6) for the lymphoma patients and 11.1 x 10(6) for the breast cancer patients. The mean time to recover > or = 0.5 x 10(9)/l granulocytes and > or = 20 x 10(9)/l platelets after reinfusion of stem cells was 10 days and 11.7 days respectively for the lymphoma patients, while the breast cancer patients engrafted at day 8.6 and day 9.3. No severe treatment-related complications were observed.

Adult↗
PubMed2006

Recent translational research: stem cells as the roots of breast cancer.

Common phenotypes of cancer and stem cells suggest that breast cancers arise from stem cells. Breast epithelial cells with stem cell phenotypes have been shown to be more susceptible to immortalization and neoplastic transformation. Breast tumor stem cells with CD44+/CD24-/lowLineage- markers have been isolated. The role of these cells in tumor progression and clinical outcome is not clear. The relationship between breast stem cell and tumor stem cell may be elucidated by further studies of carcinogenesis of nonadherent mammosphere cells with stem cell features and by derivation of CD44+/CD24-/low cells from an adherent breast epithelial stem cell type.

Breast Neoplasms↗
PubMed2005

Gastrointestinal stem cells and cancer: bridging the molecular gap.

Cancer is believed to be a disease involving stem cells. The digestive tract has a very high cancer prevalence partly owing to rapid epithelial cell turnover and exposure to dietary toxins. Work on the hereditary cancer syndromes including familial adenomatous polyposis (FAP) has led to significant advances, including the adenoma-carcinoma sequence. The initial mutation involved in this stepwise progression is in the "gatekeeper" tumor suppressor gene adenomatous polyposis coli (APC). In FAP somatic, second hits in this gene are nonrandom events, selected for by the position of the germ-line mutation. Extensive work in both the mouse and human has shown that crypts are clonal units and mutated stem cells may develop a selective advantage, eventually forming a clonal crypt population by a process called "niche succession." Aberrant crypt foci are then formed by the longitudinal division of crypts into two daughter units--crypt fission. The early growth of adenomas is contentious with two main theories, the "top-down" and "bottom-up" hypotheses, attempting to explain the spread of dysplastic tissue in the bowel. Initial X chromosome inactivation studies suggested that colorectal tumors were monoclonal; however, work on a rare XO/XY human patient with FAP and chimeric Min mice showed that 76% of adenomas were polyclonal. A reduction in tumor multiplicity in the chimeric mouse model has been achieved by the introduction of a homozygous tumor resistance allele. This model has been used to suggest that short-range interaction between adjacent initiated crypts, not random polyp collision, is responsible for tumor polyclonality.

Adenomatous Polyposis Coli↗
PubMed2006

Inflammatory cytokines predominate in cases of tumor regression after hematopoietic stem cell transplantation for solid cancer.

Allogeneic hematopoietic stem cell transplantation (SCT) has recently been presented as promising immunotherapy against renal cell, colon, ovarian, breast, and primary liver cancer. Because clinical results demonstrate a variable effect on metastases, we studied whether there is an association between the clinical response and free cytokines in serum. Two patients with metastatic colorectal and 4 with renal cell cancer underwent allogeneic SCT. Conditioning included fludarabine (30 mg/m2) for 3 or 5 days, using sibling or matched unrelated donors, respectively, followed by 2 Gy total body irradiation (n=5) or cyclophosphamide (60 mg/kg) for 2 days (n=1). Antithymoglobuline (4 mg/kg) was given to patients with matched unrelated donors (n=3). Immunosuppression was cyclosporin A, combined with mycophenolate mofetil (n=5) or methotrexate (n=1). The tumor load was examined by computer tomography of the thorax and abdomen before and 3, 6, 9, and 12 months after SCT. Free cytokines in serum were analyzed using enzyme-linked immunosorbent assay. In each patient, the ratio between inflammatory (I) and anti-I cytokines was calculated. No statistical significance was found between the cytokine ratio in correlation to the tumor load according to international response evaluation criteria in solid tumors criteria. In contrast, tumor regression was found to correlate with dominating I cytokine levels in 5/7 occasions, compared with 1/12 of cases with anti-I cytokines using our local method focusing on metastases in lungs, lymph nodes, and liver (P=.01). Thus, an increased level of I cytokines possibly mirrors tumor killing induced by type 1 T-cell response. Furthermore, anti-I cytokines might inhibit cytotoxic cells from exerting the antitumor effect of allogeneic SCT.

Aged↗
PubMed2004

From stem cells to cancer: balancing immortality and neoplasia.

In this issue of Oncogene, Serakinci et al show that adult stem cells can be targets for neoplastic transformation. After transducing human adult mesenchymal stem cells (hMSC) with the telomerase hTERT gene, and growing them for many population doublings in culture, Serakinci et al observed that the transduced cells developed characteristics consistent with transformation including loss of contact inhibition, anchorage independence and tumour formation in mice. Underlying these changes were alterations to genes involved in cell cycle regulation and senescence as well as oncogene activation. The importance of these observations is twofold. Firstly, showing that stem cells can become tumours raises a note of caution for stem cell therapeutics. Secondly, the findings lend support to the stem cell hypothesis of cancer development, and provide an experimental system in which the tantalizing hint of new diagnostic, prognostic, and therapeutic opportunities offered by this concept can be explored further.

Adult↗
PubMed2005

The role of TGF-beta and Wnt signaling in gastrointestinal stem cells and cancer.

The past three decades have seen an unremitting quest to identify and understand gastrointestinal stem cells, their plasticity in differentiating across cell types, as well as their role in normal, regenerative, and cancer cells. A fascinating hallmark of stem cells is their ability to undergo assymetric cell division, which entails replication of the DNA followed by division of the nucleus and partitioning of the cytoplasm to yield two different daughter cells: a stem cell as well as a committed progenitor cell, the latter proliferating into differentiated progeny. We are only just beginning to understand how normally quiescent, tissue-specific stem cells interpret a vast array of signals to develop into the gastrointestinal system. These signaling pathways include the transforming growth factor-beta (TGF-beta) superfamily, Wnt, FGFs, Hedgehog, Hox proteins that originate from surrounding mesodermal/stromal tissue as well as endodermal/epithelial tissue. TGF-beta and wnt proteins are key morphogens that ultimately influence cell division and cell fate, so that gut endodermal stem cells enter the cell cycle, and undergo cell division that ultimately leads to differentiated cells such as functional hepatocytes, gastric parietal cells, or gut epithelial cells. Disruptions and errors in this process usually lead to tissue-specific gastrointestinal cancers such as hepatocellular cancers, gastric adenocarcinomas, and colonic adenocarcinomas. An increasingly complex and coherent view of stem/progenitor cell signaling networks, which coordinate cell growth, proliferation, stress management, and survival, is helping to define the fragile areas where malignancies are likely to develop and shows promise for the development of better cancer therapies.

Animals↗
PubMed2004

A molecular view of stem cell and cancer cell self-renewal.

With the recent advances in cell biology and molecular genetics, scientists were able to isolate and culture tissue-specific stem cells from various sources and define their properties. The challenge has now shifted to understanding the genetic programs controlling the stem cell state, i.e. self-renewal and multipotential. Cracking the molecular codes that govern the stem cell state turns out to be a difficult task. This is in part because a single gene may exhibit distinct activities when expressed in different cell types. Comprehending the cell-context dependent readout of any given gene requires an integrated knowledge of the complex cellular machinery, a platform which can be provided by the research on stem cells. This review is an attempt to formulate a model for the self-renewal machinery operating in stem cells and cancer cells. Insight into this issue at the molecular and cellular levels will no doubt facilitate the realization of the stem cell potential in both regenerative medicine and anticancer therapy.

Cell Culture Techniques↗