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PubMed2005

Progression of myelodysplasia to acute lymphoblastic leukaemia: implications for disease biology.

Myelodysplastic syndrome (MDS) comprises a group of clonal haematopoietic disorders characterized by peripheral blood cytopenias, bone marrow hypercellularity, and abnormal blood cell differentiation. Approximately 30% of cases of MDS eventually progress to acute myelogenous leukemia (AML), while progression of MDS into acute lymphoblastic leukemia (ALL) is rare. In this report, we describe a case of MDS that progressed to ALL, and review the 21 previously reported cases of MDS to ALL transformation. We review the cancer stem cell model and its application to these disorders, and discuss the implications of the rarity of transformation of MDS to ALL for the biology of MDS and the pathogenesis of ALL.

Aged↗

PubMed2026

Oxidative stress and cancer: current insights and therapeutic implications.

OXIDATIVE STRESS: good or evil? Oxidative stress occurs when the balance between reactive oxygen species (ROS) and antioxidant defenses shifts toward an excess of ROS; while essential in physiological processes, it plays a context-dependent role in cancer, contributing to both the promotion and inhibition of tumorigenesis. Small to moderate amounts of ROS activate pathways supporting tumor progression and proliferation, while large amounts lead to genomic instability and cell death. ROS are generated endogenously and exogenously. In cancer, ROS activate pathways that prompt tumor development (KRAS, MYC, PI3K-Akt-mTOR) and block tumor suppressors (p53, BRCA1), allowing tumorigenesis and drug resistance. They also modulate the tumor microenvironment (TME) by altering tumor, stromal and immune cell interactions, which initiate angiogenesis, epithelial-mesenchymal transition (EMT), inflammation and metastasis. Myeloid-derived suppressor cells (MDSCs) and cancer-associated fibroblasts (CAFs) contribute to ROS-driven immunosuppression. Cancer cells mainly rely on glycolysis and oxidative phosphorylation (OXPHOS) to sustain their energetic and metabolic requirements. Generated ROS act as metabolic byproducts and signaling molecules supporting proliferation and tumorigenesis. Cancer stem cells (CSCs) produce low ROS levels by activating antioxidant pathways and mitochondria remodeling, ensuring recurrence and persistence. There is a redox duality that presents challenges and opportunities for therapies. Pro-oxidant approaches attempt to overwhelm the tumor's defenses, while antioxidants preserve healthy tissues. Advances in targeted redox modulation with immunotherapies improve therapy effectiveness. We propose a new "Adaptive Directed Redox Therapy" (ADRT), which involves a dynamic, feedback-controlled methodology that alternates pro- and antioxidant phases to selectively collapse tumor redox balance while preserving normal tissues.

Humans↗

PubMed2006

Mechanisms leading to the development of hormone-resistant prostate cancer.

Advanced and metastatic prostate cancers remain potentially lethal tumors. Although androgen deprivation therapy remains the most effective treatment, patients who progress to androgen independence die of their disease. This article focuses on the mechanisms by which hormone resistance develops, including the reactivation of androgen receptor during androgen deprivation therapy, the role of cancer stem cells, and the emergence of epithelial-mesenchymal transition cells, which have increased metastatic potential. It is through an enhanced understanding of these mechanisms that new therapies can be developed to combat this disease.

Androgen Antagonists↗

PubMed2006

Sentinel-lymph-node biopsy as a staging procedure in breast cancer: update of a randomised controlled study.

BACKGROUND: In women with breast cancer, sentinel-lymph-node biopsy (SLNB) provides information that allows surgeons to avoid axillary-lymph-node dissection (ALND) if the SLN does not have metastasis, and has a favourable effect on quality of life. Results of our previous trial showed that SLNB accurately screens the ALN for metastasis in breast cancers of diameter 2 mm or less. We aimed to update this trial with results from longer follow-up. METHODS: Women with breast tumours of diameter 2 cm or less were randomly assigned after breast-conserving surgery either to SLNB and total ALND (ALND group), or to SLNB followed by ALND only if the SLN was involved (SLN group). Analysis was restricted to patients whose tumour characteristics met eligibility criteria after treatment. The main endpoints were the number of axillary metastases in women in the SLN group with negative SLNs, staging power of SLNB, and disease-free and overall survival. FINDINGS: Of the 257 patients in the ALND group, 83 (32%) had a positive SLN and 174 (68%) had a negative SLN; eight of those with negative SLNs were found to have false-negative SLNs. Of the 259 patients in the SLN group, 92 (36%) had a positive SLN, and 167 (65%) had a negative SLN. One case of overt clinical axillary metastasis was seen in the follow-up of the 167 women in the SLN group who did not receive ALND (ie, one false-negative). After a median follow-up of 79 months (range 15-97), 34 events associated with breast cancer occurred: 18 in the ALND group, and 16 in the SLN group (log-rank p=0.6). The overall 5-year survival of all patients was 96.4% (95% CI 94.1-98.7) in the ALND group and 98.4% (96.9-100) in the SLN group (log-rank p=0.1). INTERPRETATION: SLNB can allow total ALND to be avoided in patients with negative SLNs, while reducing postoperative morbidity and the costs of hospital stay. The finding that only one overt axillary metastasis occurred during follow-up of patients who did not receive ALND (whereas eight cases were expected) could be explained by various hypotheses, including those from cancer-stem-cell research.

Adult↗

PubMed2006

Neoadjuvant chemotherapy in women with large and locally advanced breast cancer: chemoresistance and prediction of response to drug therapy.

Patients with large and locally advanced breast cancer (LLABC) present with a therapeutic challenge and undergo multimodality treatment. Many such patients receive neoadjuvant chemotherapy (NAC) prior to surgery. However, a number of these patients do not respond well to NAC and only a percentage (usually less than 30%) obtains a complete or optimal response. A range of mechanisms are believed to be involved in this chemoresistance, including ATP binding cassette (ABC) transporter overexpression, dysregulation of apoptosis and possibly increased numbers of cancer stem cells. The chemoresistant processes may be due to more than one mechanism. The ability to predict a response to NAC would be beneficial, targeting expensive and toxic drug treatment to those likely to respond and providing a therapeutic strategy for further post-operative chemotherapy. Currently, many biomarkers have been studied with a view to establishing a predictor of response. However, no single biomarker appears to be effective. Genomics is a novel biotechnological process which is being used to predict response to drug therapy; this work is currently at an early stage of development

Antineoplastic Agents↗

PubMedDate not supplied

Immunotherapy. I: Cytokine gene transfer strategies.

The cytokine approach to gene therapy of cancer stems from early studies of direct, repeated injection of recombinant cytokines at the tumor site, and extension of the bystander effect that enables a few cytokine gene transduced cells in a tumor to bring about its total destruction. This effect can be extended through the immune system, since cytokine-activated regression of a small mass of tumor cells can afford systemic protection. Transduced cells used as a vaccine provide a local concentration of both cytokine and tumor antigens. Cytokines sustain antigen uptake and presentation by increasing the immunogenic potential of the environment through the recruitment of antigen presenting cells and leukocytes, and activation of a cascade of events which amplify and tone up the efficacy of a vaccine. The promises and difficulties of this approach are discussed by considering what is still missing from experimental studies and what can best be done as soon as possible in animals and humans to reach compelling conclusions.

Animals↗

PubMed2006

Targeting gene-virotherapy of cancer and its prosperity.

Gene and viral therapies for cancer have shown some therapeutic effects, but there has been a lack of real breakthrough. To achieve the goal of complete elimination of tumor xenograft in animal models, we have developed a new strategy called Targeting Gene-Virotherapy of Cancer, which aims to combine the advantages of both gene therapy and virotherapy. This new strategy has produced stronger anti-tumor effects than either gene or viral therapy alone. A tumor-specific replicative adenovirus vector, designated as ZD55, was constructed by deletion of the 55kDa E1B region of adenovirus. The resulting viral construct not only retains a similar function to ONYX-015 by specifically targeting p53 negative tumors, but also allows for the insertion of various therapeutic genes to form appropriate ZD55 derivatives due to the newly introduced cloning site, a task not feasible with the original ONYX-015 virus. We showed that the anti-tumor effect of one such derivative, ZD55-IL-24, is at least 100 times more potent than that of either ZD55 virotherapy or Ad-IL-24 gene therapy. Nevertheless, complete elimination of tumor mass by the use of ZD55-IL-24 was only observed in some but not all mice, indicating that one therapeutic gene was not sufficient to "cure" these mice. When genes with complementary or synergetic effects were separately cloned into the ZD55 vector and used in combination (designated as the Dual Gene Therapy strategy), much better results were obtained; and it was possible to achieve complete elimination of all the xenograft tumor masses in all mice if two suitable genes were chosen. More comprehensive studies based on this new strategy will likely lead to a protocol for clinical trial. Finally, the concept of Double Controlled Targeting Virus-Dual Gene Therapy for cancer treatment, and the implication of the recent progress in cancer stem cells are also discussed.

Adenoviridae↗

PubMed2004

Concepts of human leukemic development.

Two fundamental problems in cancer research are identification of the normal cell within which cancer initiates and identification of the cell type capable of sustaining the growth of the neoplastic clone. There is overwhelming evidence that virtually all cancers are clonal and represent the progeny of a single cell. What is less clear for most cancers is which cells within the tumor clone possess tumorigenic or 'cancer stem cell' (CSC) properties and are capable of maintaining tumor growth. The concept that only a subpopulation of rare CSC is responsible for maintenance of the neoplasm emerged nearly 50 years ago. Testing of this hypothesis is most advanced for the hematopoietic system due to the establishment of functional in vitro and in vivo assays for stem and progenitor cells at all stages of development. This body of work led to conclusive proof for CSC with the identification and purification of leukemic stem cells capable of repopulating NOD/SCID mice. This review will focus on the historical development of the CSC hypothesis, the mechanisms necessary to subvert normal developmental programs, and the identification of the cell in which these leukemogenic events first occur.

Acute Disease↗

PubMed2006

PDGF essentially links TGF-beta signaling to nuclear beta-catenin accumulation in hepatocellular carcinoma progression.

The cooperation of Ras - extracellular signal-regulated kinase/mitogen-activated protein kinase and transforming growth factor (TGF)-beta signaling provokes an epithelial to mesenchymal transition (EMT) of differentiated p19(ARF) null hepatocytes, which is accompanied by a shift in malignancy and gain of metastatic properties. Upon EMT, TGF-beta induces the secretion and autocrine regulation of platelet-derived growth factor (PDGF) by upregulation of PDGF-A and both PDGF receptors. Here, we demonstrate by loss-of-function analyses that PDGF provides adhesive and migratory properties in vitro as well as proliferative stimuli during tumor formation. PDGF signaling resulted in the activation of phosphatidylinositol-3 kinase, and furthermore associated with nuclear beta-catenin accumulation upon EMT. Hepatocytes expressing constitutively active beta-catenin or its negative regulator Axin were employed to study the impact of nuclear beta-catenin. Unexpectedly, active beta-catenin failed to accelerate proliferation during tumor formation, but in contrast, correlated with growth arrest. Nuclear localization of beta-catenin was accompanied by strong expression of the Cdk inhibitor p16(INK4A) and the concomitant induction of the beta-catenin target genes cyclin D1 and c-myc. In addition, active beta-catenin revealed protection of malignant hepatocytes against anoikis, which provides a prerequisite for the dissemination of carcinoma. From these data, we conclude that TGF-beta acts tumor progressive by induction of PDGF signaling and subsequent activation of beta-catenin, which endows a subpopulation of neoplastic hepatocytes with features of cancer stem cells..

Anoikis↗

PubMed2005

Hsp90 and environmental impacts on epigenetic states: a model for the trans-generational effects of diethylstibesterol on uterine development and cancer.

Hsp90 is a chaperone for over 100 'client proteins' in the cell, most of which are involved in signaling pathways. For example, Hsp90 maintains several nuclear hormone receptors, such as the estrogen receptor (ER), as agonist-receptive monomers in the cytoplasm. In the presence of agonist, Hsp90 dissociates and the receptors dimerize, enter the nucleus and ultimately activate transcription of the target genes. Increasing evidence suggests that Hsp90 also has a role in modifying the chromatin conformation of many genes. For example, Hsp90 has recently been shown to increase the activity of the histone H3 lysine-4 methyltransferase SMYD3, which activates the chromatin of target genes. Further evidence for chromatin-remodeling functions is that Hsp90 acts as a capacitor for morphological evolution by masking epigenetic variation. Release of the capacitor function of Hsp90, such as by environmental stress or by drugs that inhibit the ATP-binding activity of Hsp90, exposes previously hidden morphological phenotypes in the next generation and for several generations thereafter. The chromatin-modifying phenotypes of Hsp90 have striking similarities to the trans-generational effects of the ER agonist diethylstilbesterol (DES). Prenatal and perinatal exposure to DES increases the predisposition to uterine developmental abnormalities and cancer in the daughters and granddaughters of exposed pregnant mice. In this review, we propose that trans-generational epigenetic phenomena involving Hsp90 and DES are related and that chromatin-mediated WNT signaling modifications are required. This model suggests that inhibitors of Hsp90, WNT signaling and chromatin-remodeling enzymes might function as anticancer agents by interfering with epigenetic reprogramming and canalization in cancer stem cells.

Animals↗

PubMed2004

Co-receptor antagonists as HIV-1 entry inhibitors.

PURPOSE OF REVIEW: A new mechanistic understanding of how HIV-1 enters cells has emerged recently, and these discoveries are now being translated into novel therapeutic agents. Along with CD4, HIV-1 requires a chemokine receptor, CCR5 or CXCR4, as an entry co-receptor, and differential co-receptor selectivity is an important determinant of viral diversity and pathogenesis. CCR5 and CXCR4 blockers have been the focus of much research and are now entering clinical trials. RECENT FINDINGS: Several CCR5 antagonists with anti-HIV-1 activity have been developed, including small-molecule agents, monoclonal antibodies and modified chemokines. At least four small-molecule and one antibody CCR5 inhibitor are in various stages of preclinical and clinical testing. Most or all infected individuals harbor CCR5-using variants, and promising findings have been reported from very preliminary clinical studies. CXCR4 antagonists under development include small-molecule and short-peptide inhibitors. Only a subset of late-stage individuals harbor CXCR4-using strains, and early clinical studies of CXCR4 inhibition showed some evidence of suppression in certain individuals. SUMMARY: Chemokine receptor antagonists offer great promise as a much-needed new class of antiviral agent. They also raise questions that are unique to agents targeting these cellular receptors, including whether drug resistance will lead to variants with altered co-receptor selectivity, the tolerability of chronically blocking receptors involved in inflammation (CCR5, CXCR4) or essential in development and hematopoesis (CXCR4), and the role of co-receptor phenotyping in selecting blocking agents. In addition to HIV-1 infection, these drugs may also have utility in inflammation, cancer, stem cell transplant and other areas.

Anti-HIV Agents↗

PubMed2006

Kinase mutations in cancer: chinks in the enemy's armour?

PURPOSE OF REVIEW: Over the past few years, a revolution has transformed the oncology field. This revolution is characterized by two main features. The first is the introduction of the concept of individualized cancer therapy. The second is the development of drugs targeting molecules selectively altered in tumours. This review analyses these aspects by looking at the role that altered kinases and their inhibitors have played in this historical process. RECENT FINDINGS: Tumour progression is the result of the sequential accumulation of mutations in genes monitoring the rates of cell birth and cell death. The molecular profiling of cancers has shown that protein and lipid kinases are frequently altered in tumour cells. In most cases, these alterations translate in constitutively active proteins, which are amenable of therapeutic targeting. Intriguingly, even 'established' cancer cells remain somewhat 'addicted' to the deregulated activity of mutated kinases. This feature appears to be the basis for the ability of kinase inhibitors in controlling the development of a number of cancers. The therapeutic efficacy of kinase inhibitors is impaired by the emergence of tumour cells carrying 'resistance' mutations. SUMMARY: Many oncogenes are mutated kinase genes. In most cases, the mutations result in the constitutive activation of the affected kinase that can be pharmacologically inhibited. Unfortunately, upon treatment with kinase inhibitors, resistant clones develop rapidly, impairing their therapeutic effect. Strategies to overcome resistance are discussed as well as the possibility to target kinases regulating cancer stem cells.

Drug Resistance, Neoplasm↗

PubMed2006

EGFR regulates the side population in head and neck squamous cell carcinoma.

OBJECTIVE: To identify the presence of side population (SP) cells in established head and neck squamous carcinoma cell (HNSCC) lines and to determine the role of EGFR in the regulation of the side population of these cells. METHODS: SP cells were identified using flow cytometry analysis by the ability of these cells to extrude the Hoechst 33342 dye via the drug transporter BCRP1/ABCG2. Effect of EGFR on the side population was determined also by difference in Hoechst extrusion and by immunofluorescence. Immunohistochemical staining was performed to show the presence of the BCRP1/ABCG2 transporter and the phosphorylated form of EGFR in HNSCC tissue. RESULTS: SP cells are present in HNSCC cell lines. With the Hoechst 33342 extrusion assay, SP cells were found to comprise an average of 0.69% of the UMSCC10B cells and 0.91% of HN12 cells. Addition of the EGF ligand increased the SP population while inactivation of the EGFR kinase by Iressa significantly decreased SP. CONCLUSION: In established head and neck squamous cell carcinoma cell lines, SP cells were found using methods that determine expression and function of the drug transporter BCRP1/ABCG2. Activation of EGFR, a gene implicated in tumorigenesis in HNSCC leads to increased SP, and conversely, inhibition of EGFR leads to decrease in SP. This finding could help explain the role of EGFR in regulating cancer stem cells and thus tumorigenesis in HNSCC.

ATP Binding Cassette Transporter, Subfamily G, Mem↗

PubMed2005

An update on oligodendroglial neoplasms.

PURPOSE OF REVIEW: The most widely accepted brain tumor classification system remains morphology-based but the increasing knowledge of the molecular pathogenesis of oligodendroglial tumors has spurred translational research yielding new diagnostic and therapeutic paradigms. These data have accumulated rapidly and, in combination with exciting new insights in the cellular origin of these tumors, necessitate a review. RECENT FINDINGS: 'Cancer stem cells' have been identified in gliomas. Further study of these cells will not only provide information on the cellular origin and pathogenesis of these tumors but may also give rise to new treatments that target a cell pool not amenable to current therapeutic strategies. Molecular tumor characteristics have been correlated with imaging findings, treatment response and prognosis. This has enabled neuro-oncologists to take a risk-stratified approach to patients with oligodendrogliomas that optimizes treatment efficacy and minimizes toxicity. Furthermore, more accurate epidemiological data have become available from population-based studies. SUMMARY: In spite of remarkable progress over the last 15 years, these tumors remain incurable. The search for a cure has to go on, while currently available multidisciplinary treatments are refined.

Brain Neoplasms↗

PubMed2005

Mouse models for human lung cancer.

In recent years several new mouse models for lung cancer have been described. These include models for both non-small-cell lung cancer (NSCLC) and small-cell lung cancer (SCLC). Tumorigenesis in these conditional mouse tumor models can be initiated in adult mice through Cre-recombinase-induced activation of oncogenic mutations in a subset of the cells. They present a marked improvement over mouse models that depend on carcinogen induction of tumors. These models permit us to study the consecutive steps involved in initiation and progression and allow us to address questions like the cell of origin, and the role of cancer stem cells in the maintenance of these tumors. They now need to be validated as suitable preclinical models for intervention studies in which questions with respect to therapy response and resistance can be addressed.

Animals↗

PubMed2005

Combined fibrolamellar carcinoma and cholangiocarcinoma exhibiting biphenotypic antigen expression: a case report.

Fibrolamellar carcinoma (FLC), a variant of hepatocellular carcinoma (HCC), very rarely occurs in association with cholangiocarcinoma (CC). This report describes the first case of FLC coexisting with CC (FLC-CC) from Japan. Although the major part of the tumour located in the right lobe of the liver showed the typical features of FLC, CC was admixed with the FLC, not only in the primary hepatic tumour, but also in the lymph node metastases. Immunohistochemical analysis revealed that, although carcinoembryonic antigen (CEA), which can be detected with monoclonal antibodies in the cytoplasm and the cell surface of CC cells but not HCC cells, was expressed in only the CC cells in the primary tumour, it was expressed extensively in the cytoplasm of both CC and FLC cells in the metastatic and recurrent tumours. Furthermore, Hep Par 1, a hepatocyte specific antigen, was also expressed in both the FLC and CC cells. These findings suggest that, in this case, both FLC and CC were possibly derived from the same cancer stem cell with the capacity to differentiate into both hepatocytes and bile duct epithelium, and that both the cellular components, therefore, exhibited biphenotypic antigen expression.

Adolescent↗

PubMed2004

26th Annual San Antonio Breast Cancer Symposium, San Antonio, Texas, USA, 3-6 December 2003: update on preclinical and translational research.

The San Antonio Breast Cancer Symposium is the largest annual meeting devoted solely to breast cancer research. The late William L McGuire's vision for this meeting was to stimulate 'translational research', many years before this term became popular. In this way, the San Antonio Breast Cancer Symposium represents a forum in which basic and clinical researchers present their research side by side. Each year sees the continued evolution of our understanding of the basic mechanisms of breast cancer initiation and progression, and the clinical application of this knowledge. Major topics of discussion at the symposium this year were the cell cycle, new evolving concepts of estrogen receptor action, breast cancer stem cells, new predictive and prognostic markers (including microarray studies), and continued exploration of the mechanisms of drug resistance. This report will summarize preclinical and translational highlights from the meeting.

Breast Neoplasms↗

PubMed1996

Telomerase is activated in the prostate and seminal vesicles of the castrated rat.

Telomeres, the repetitive non-coding DNA sequences found at the ends of all eukaryotic chromosomes, shorten with each cell division. It has been proposed that telomere shortening may be the counting element of a mitotic clock that keeps track of cell divisions; with shortening to a critical length acting as a senescence signal underlying cellular aging. The enzyme telomerase functions to maintain telomere length, thus allowing unlimited cell division, and has been associated with cellular immortalization and cancer. Stem cells have large, perhaps unlimited, replicative capacities. Since these cells are potentially immortal, we reasoned that they might posses active telomerase. We therefore assayed for telomerase activity in the stem cell enriched pools of the androgen-depleted sex accessory tissues in the castrated male rat. Following castration, the ventral prostate and seminal vesicles of the rat involute, losing approximately 90% of their cells by 21 days. These residual glands persist, and are enriched for stem cells, being capable of fully regenerating these glands if testosterone is re-introduced into the animal. We assayed telomerase activity in extracts from normal, involuted, and regenerating ventral prostate and seminal vesicles. Normal glands were found to be telomerase negative, whereas telomerase activity appeared as these glands involuted following castration. Conversely, telomerase activity disappeared during testosterone-induced regeneration of these residual glands. These results provide strong evidence for the ability of androgen to negatively-regulate telomerase activity in stem cell populations of the rat ventral prostate and seminal vesicles. and represent the first in vivo model system for the modulation of telomerase activity.

Animals↗