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Results for “Cancer stemness”

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PubMed2006

The cancer stem cell: evidence for its origin as an injured autoreactive T cell.

This review explores similarities between lymphocytes and cancer cells, and proposes a new model for the genesis of human cancer. We suggest that the development of cancer requires infection(s) during which antigenic determinants from pathogens mimicking self-antigens are co-presented to the immune system, leading to breaking T cell tolerance. Some level of autoimmunity is normal and necessary for effective pathogen eradication. However, autoreactive T cells must be eliminated by apoptosis when the immune response is terminated. Apoptosis can be deficient in the event of a weakened immune system, the causes of which are multifactorial. Some autoreactive T cells suffer genomic damage in this process, but manage to survive. The resulting cancer stem cell still retains some functions of an inflammatory T cell, so it seeks out sites of inflammation inside the body. Due to its defective constitutive production of inflammatory cytokines and other growth factors, a stroma is built at the site of inflammation similar to the temporary stroma built during wound healing. The cancer cells grow inside this stroma, forming a tumor that provides their vascular supply and protects them from cellular immune response. As cancer stem cells have plasticity comparable to normal stem cells, interactions with surrounding normal tissues cause them to give rise to all the various types of cancers, resembling differentiated tissue types. Metastases form at an advanced stage of the disease, with the proliferation of sites of inflammation inside the body following a similar mechanism. Immunosuppressive cancer therapies inadvertently re-invigorate pathogenic microorganisms and parasitic infections common to cancer, leading to a vicious circle of infection, autoimmunity and malignancy that ultimately dooms cancer patients. Based on this new understanding, we recommend a systemic approach to the development of cancer therapies that supports rather than antagonizes the immune system.

Animals↗
PubMed2006

Cancer stem cells and differentiation therapy.

Cancers arise from stem cells in adult tissues and the cells that make up a cancer reflect the same stem cell --> progeny --> differentiation progression observed in normal tissues. All adult tissues are made up of lineages of cells consisting of tissue stem cells and their progeny (transit-amplifying cells and terminally differentiated cells); the number of new cells produced in normal tissue lineages roughly equals the number of old cells that die. Cancers result from maturation arrest of this process, resulting in continued proliferation of cells and a failure to differentiate and die. The biological behavior, morphological appearance, and clinical course of a cancer depend on the stage of maturation at which the genetic lesion is activated. This review makes a comparison of cancer cells to embryonic stem cells and to adult tis sue stem cells while addressing two basic questions: (1) Where do cancers come from?, and (2) How do cancers grow? The answers to these questions are critical to the development of approaches to the detection, prevention, and treatment of cancer.

Animals↗
PubMed2025

Connexin 43 drives glioblastoma cancer stem cell phenotypes through a WNK lysine-deficient protein kinase 1-c-MYC signaling axis.

The coordination of cellular processes such as growth and survival relies on communication between cells through gap junctions. Connexin proteins comprise gap junctions and also function to mediate protein-protein interactions and communication with the extracellular space via hemichannels. Despite their essential roles, connexin function in cancer is context dependent, with connexin 43 (Cx43) reported to both promote and suppress tumor growth in glioblastoma, the most common primary malignant brain tumor. Here, we detect primarily intracellular expression of Cx43 in glioblastoma patient-derived cancer stem cells and demonstrate that Cx43 is essential for their survival, self-renewal, and tumor initiation. Mechanistically, Cx43 depletion reduces c-MYC expression through reduced levels of the upstream mediator WNK lysine-deficient protein kinase 1 (WNK1). WNK1 depletion phenocopies Cx43 knockdown and reduces c-MYC expression and tumor initiation. Together, these results define a signaling axis downstream of Cx43 that promotes tumor growth and cancer stem cell phenotypes in glioblastoma.

Connexin 43↗
PubMed2005

Retrovirus silencing and vector design: relevance to normal and cancer stem cells?

An obstacle confronting gene therapy in stem cells is transcriptional silencing of the vector. Here, we discuss recent data indicating that oncoretrovirus and lentivirus vectors are silenced by multiple epigenetic pathways that result in DNA methylation and histone modifications. Both vector types can be variegated in stem cells and expression is often extinguished during differentiation. We propose a novel model of retrovirus silencing in which epigenetic pathways compete to recruit histone deacetylases, de novo methyltransferases, histone H1 and MeCP2 to the provirus. These chromatin modifications may act in concert with heterochromatin at or near the integration site to establish silencing or variegation respectively. Retrovirus vector designs for stem cells should delete virus silencer elements, incorporate strong positive regulatory elements and insulators, and avoid non-mammalian reporter genes. In addition, cancer stem cells that continually repopulate a growing tumour may share silencing pathways with normal stem cells. Ultimately, optimized vector designs may prove to be valuable tools for gene therapy of both normal and cancer stem cells.

Epigenesis, Genetic↗
PubMed2006

Identifying cancer stem cells in solid tumors: case not proven.

Building on studies of leukemia, a number of recent articles have reported data suggesting that cancer stem cells could be isolated from solid human cancers. Some of these reports have speculated that the isolation of these cells will allow the identification of the specific molecular properties that can be targeted for therapeutic purposes. Although previous work with animal model systems also suggests the presence of stem cells in solid tumors, there remain many uncertainties, both theoretical and technical, about the interpretation of the current results. The case that a small proportion of cells in solid tumors are specific cancer stem cells and that these cells can be successfully identified and isolated has not yet been proven.

Animals↗
PubMed2006

Breast cancer, stem cells and prospects for therapy.

The mammary epithelium contains multipotent stem cells that give rise to all differentiated cell types present within the tissue. Mammary epithelial stem cells have been prospectively purified from dissociated mammary epithelium on the basis of cell surface antigen expression. It has become apparent in recent years that for breast cancer and other malignancies only a small proportion of tumour cells--'cancer stem cells'--have the capacity for extensive proliferation and transferral of the tumour. We review the evidence for breast cancer stem cells, we consider their relationship to mammary epithelial stem cells and we examine the implications for current and future therapeutic strategies.

Breast↗
PubMed2005

Cancer stem cells: lessons from leukemia.

A fundamental problem in cancer research is identification of the cell type capable of initiating and sustaining growth of the tumor--the cancer stem cell (CSC). While the existence of CSCs was first proposed over 40 years ago, only in the past decade have these cells been identified and characterized in hematological malignancies. Recent studies have now described CSCs in solid tumors of the breast and brain, raising the possibility that such cells are at the apex of all neoplastic systems. An appreciation of the biological distinctness of CSCs is crucial not only for the design of studies to understand how tumorigenic pathways operate but also for the development of specific therapies that effectively target these cells in patients.

Animals↗
PubMed2004

Cancer stem cells in nervous system tumors.

Most current research on human brain tumors is focused on the molecular and cellular analysis of the bulk tumor mass. However, evidence in leukemia and more recently in solid tumors such as breast cancer suggests that the tumor cell population is heterogeneous with respect to proliferation and differentiation. Recently, several groups have described the existence of a cancer stem cell population in human brain tumors of different phenotypes from both children and adults. The finding of brain tumor stem cells (BTSCs) has been made by applying the principles for cell culture and analysis of normal neural stem cells (NSCs) to brain tumor cell populations and by identification of cell surface markers that allow for isolation of distinct tumor cell populations that can then be studied in vitro and in vivo. A population of brain tumor cells can be enriched for BTSCs by cell sorting of dissociated suspensions of tumor cells for the NSC marker CD133. These CD133+ cells, which also expressed the NSC marker nestin, but not differentiated neural lineage markers, represent a minority fraction of the entire brain tumor cell population, and exclusively generate clonal tumor spheres in suspension culture and exhibit increased self-renewal capacity. BTSCs can be induced to differentiate in vitro into tumor cells that phenotypically resembled the tumor from the patient. Here, we discuss the evidence for and implications of the discovery of a cancer stem cell in human brain tumors. The identification of a BTSC provides a powerful tool to investigate the tumorigenic process in the central nervous system and to develop therapies targeted to the BTSC. Specific genetic and molecular analyses of the BTSC will further our understanding of the mechanisms of brain tumor growth, reinforcing parallels between normal neurogenesis and brain tumorigenesis.

Adult↗
PubMed2005

Cancer stem cells: AMLs show the way.

The blood-related cancer leukaemia was the first disease where human CSCs (cancer stem cells), or LSCs (leukaemic stem cells), were isolated. The haematopoietic system is one of the best tissues for investigating CSCs, since the developmental hierarchy of normal blood formation is well defined. Leukaemia can now be viewed as aberrant haematopoietic processes initiated by rare LSCs that have maintained or reacquired the capacity for indefinite proliferation through accumulated mutations and/or epigenetic changes. Yet, despite their critical importance, much remains to be learned about the developmental origin of LSCs and the mechanisms responsible for their emergence in the course of the disease. This report will review our current knowledge on LSC development and finally demonstrate how these discoveries provide a paradigm for identification of CSCs from solid tumours.

Animals↗
PubMed2006

Strategies to eliminate cancer stem cells: clinical implications.

Over the past two decades, major advances in our understanding of cancer have translated into only modest increments in survival for the majority of cancer patients. Recent data suggesting cancers arise from rare self-renewing stem cells that are biologically distinct from their more numerous differentiated progeny may explain this paradox. Current anticancer therapies have been developed to decrease the bulk of the tumour mass (i.e. the differentiated cancer cells). Although treatments directed against the bulk of the cancer may produce dramatic responses, they are unlikely to result in long-term remissions if the rare cancer stem cells are also not targeted. Conversely, treatments that selectively attack cancer stem cells will not immediately eliminate the differentiated cancer cells, and might therefore be prematurely abandoned if clinical activity is judged solely by traditional response criteria that reflect changes in the bulk of the tumour. Re-examining both our pre-clinical and clinical drug development paradigms to include the cancer stem cell concept has the potential to revolutionize the treatment of many cancers.

Antineoplastic Agents↗
PubMed2006

Potential gene therapy strategies for cancer stem cells.

To be maximally effective, therapy of cancer must be directed against both the resting stem cells and the proliferating cells of the cancer. The cell populations of both normal and cancer tissues consist of resting stem cells, proliferating transit-amplifying cells, terminally differentiating cells and dying (apoptotic) cells. The difference between normal tissue renewal and growth of cancers is that some of the transit-amplifying cells in the cancer population do not mature into terminally differentiating cells, but instead continue to proliferate and do not die (maturation arrest). Because of this the number of cancer cells increase, whereas the cell population of normal tissues remains a relatively constant. Conventional radiation treatment and chemotherapy kill the actively proliferating transit- amplifying cells of the cancer. Differentiation therapy, using specific targeted inhibitors of activation, effectively induces differentiation of the proliferating transit-amplifying cancer cells. However, even if the proliferating cancer cells are completely inhibited or eliminated, the cancer stem cells may restore the transit-amplifying population, so that clinical remission is usually temporary. The hypothesis presented in this paper is that successful cancer therapy must be directed against both the resting stem cells and the proliferating cells of the cancer. This may be possible if specific stem cell signals are inhibited using gene therapy, while at the same time attacking proliferating cells by conventional radiation treatment or chemotherapy. With advances in approaches using specific inhibitory RNA, such combination therapy may now be possible, but critical problems in delivering the inhibitory effect specifically to the cancer stem cells have yet to be worked out.

Animals↗
PubMed2006

Most early disseminated cancer cells detected in bone marrow of breast cancer patients have a putative breast cancer stem cell phenotype.

PURPOSE: The presence of disseminated tumor cells (DTC) in the bone marrow of breast cancer patients is an acknowledged independent prognostic factor. The biological metastatic potential of these cells has not yet been shown. The presence of putative breast cancer stem cells is shown both in primary tumors and distant metastases. These cells with a CD44(+)CD24(-/low) phenotype represent a minor population in primary breast cancer and are associated with self-renewal and tumorigenic potential. Recognizing the potential effect of prevalence of putative stem cells among DTC, we evaluated the bone marrow DTC. EXPERIMENTAL DESIGN: We employed the double/triple-staining immunohistochemistry protocol and modified the established bone marrow cytokeratin (CK) staining protocol by adding steps for additional antigens, CD44 and/or CD24. We evaluated 50 bone marrow specimens, previously categorized as CK(+) from early breast cancer patients. CK(+) cells were examined for CD44 and CD24 expression by light microscopy, fluorescence microscopy, and spectral imaging. RESULTS: We detected the putative stem cell-like phenotype in all CK(+) specimens. The mean prevalence of putative stem/progenitor cells was 72% and median prevalence was 65% (range, 33-100%) among the overall DTC per patient, compared with primary tumors where this phenotype is reported in <10% of cells. CONCLUSIONS: This is the first evidence of the existence of the putative stem-like phenotype within the DTC in bone marrow in early breast cancer patients. All patients had a putative stem cell phenotype among the DTC and most individual DTC showed such phenotype. Future molecular characterization of these cells is warranted.

Bone Marrow↗
PubMed2004

Will cancer stem cells provide new therapeutic targets?

This review presents a brief synopsis of recent progress in the area of cancer stem cells, with emphasis on leukemia and breast cancer, and discusses potential limitations to accomplishing the ultimate goal of eradicating residual disease in cancer.

Animals↗
PubMed2007

Cancer stem cells: models and concepts.

Although monoclonal in origin, most tumors appear to contain a heterogeneous population of cancer cells. This observation is traditionally explained by postulating variations in tumor microenvironment and coexistence of multiple genetic subclones, created by progressive and divergent accumulation of independent somatic mutations. An additional explanation, however, envisages human tumors not as mere monoclonal expansions of transformed cells, but rather as complex tridimensional tissues where cancer cells become functionally heterogeneous as a result of differentiation. According to this second scenario, tumors act as caricatures of their corresponding normal tissues and are sustained in their growth by a pathological counterpart of normal adult stem cells, cancer stem cells. This model, first developed in human myeloid leukemias, is today being extended to solid tumors, such as breast and brain cancer. We review the biological basis and the therapeutic implications of the stem cell model of cancer.

Humans↗
PubMed2006

Killing time for cancer stem cells (CSC): discovery and development of selective CSC inhibitors.

Can cancer be cured or will it have to be controlled as a chronic disease? Despite a better understanding of the biology of tumour cells, the treatment of most cancers has not significantly changed for the past three decades. Are current cancer drugs targeted at the wrong kind of cells? Accumulating evidence has implicated that cancer is a disease of stem cells. In this context, a small fraction of cancer cells adopt the properties of stem cells. In some cases, the cancer stem cells (CSC) could be the close derivative of normal tissue stem cells. In either situation, the net result will be the same, in that CSC are the cells to be used as targets in the development of molecular and pharmaceutical therapies to treat and prevent human cancer. This could be a paradigm shift in the treatment of cancer, away from targeting the blast cells and towards the targeting of the CSC. A challenge to this approach will be to find a way to specifically target CSC without toxicity to normal cells. In this article, we propose how CSC can be used in therapy programs (target identification, drug discovery, etc.). Therefore, in the future, it might be possible to rid a patient of all his/her cancer cells, including the cancer stem cells.

Animals↗
PubMed2006

Brain tumors provide new clues to the source of cancer stem cells: does oncology recapitulate ontogeny?

Recent studies of leukemia and solid tumors have provided compelling evidence for the existence of cancer stem cells, but the origin of these cells remains a matter of considerable debate. By comparing the gene expression profiles of ependymomas with those of cells in the normal developing nervous system, we were able to pinpoint radial glia as candidate stem cells of this brain tumor. These data suggest strongly that ependymomas arise directly from transformed radial glia and they provide a novel method that could be used to map the cell of origin of other types of cancer.

Animals↗