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Results for “Cancer stem cells”

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PubMed2003

Identification of a cancer stem cell in human brain tumors.

Most current research on human brain tumors is focused on the molecular and cellular analysis of the bulk tumor mass. However, there is overwhelming evidence in some malignancies that the tumor clone is heterogeneous with respect to proliferation and differentiation. In human leukemia, the tumor clone is organized as a hierarchy that originates from rare leukemic stem cells that possess extensive proliferative and self-renewal potential, and are responsible for maintaining the tumor clone. We report here the identification and purification of a cancer stem cell from human brain tumors of different phenotypes that possesses a marked capacity for proliferation, self-renewal, and differentiation. The increased self-renewal capacity of the brain tumor stem cell (BTSC) was highest from the most aggressive clinical samples of medulloblastoma compared with low-grade gliomas. The BTSC was exclusively isolated with the cell fraction expressing the neural stem cell surface marker CD133. These CD133+ cells could differentiate in culture into tumor cells that phenotypically resembled the tumor from the patient. 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.

AC133 Antigen↗
PubMed2006

Redefining cellular phenotypy based on embryonic, adult, and cancer stem cell biology.

Stem cell biology has provided constant alteration if not reversal of dogma related to the understanding of the behaviors of primitive and dynamic cells. This review summarizes recent findings on dynamic changes of phenotype that accompany the in vitro growth and differentiation of not only stem and progenitor cells, but also differentiated cells derived from a variety of normal and pathological tissues. As there are examples of apparent dedifferentiation and transdifferentiation of neural cells that appear to be terminally differentiated, there is a need to reconsider elements of cellular fate choice that have relevance to neurooncology and neural repair. Recent findings of dynamic behaviors and mixed phenotype of both normal and cancer stem cells suggest that some of the diverse lineage attributes of different solid tumors may owe their existence to dynamic cellular phenotypy gone awry.

Age Factors↗
PubMed2004

Cancer stem cell biology: from leukemia to solid tumors.

The biology of stem cells and their intrinsic properties are now recognized as integral to tumor pathogenesis in several types of cancer. This observation has broad ramifications in the cancer research field and is likely to impact our understanding of the basic mechanisms of tumor formation and the strategies we use to treat cancers. A role for stem cells has been demonstrated for cancers of the hematopoietic system, breast and brain. Going forward it is likely that stem cells will also be implicated in other malignancies. Hence, a detailed understanding of stem cells and how they mediate tumor pathogenesis will be critical in developing more effective cancer therapies.

Animals↗
PubMed2005

Stem cells for lung cancer?

Stem cells are believed to be crucial players in tumor development. There is much interest in identifying those compartments that harbor stem cells involved in lung cancer, given the high incidence and recurrence rate of this disease. In this issue of Cell, Kim and colleagues describe a niche in the bronchioalveolar duct junction of adult mouse lung that harbors stem cells from which adenocarcinomas are likely to arise. They enriched, propagated, and differentiated these stem cells in vitro and found that they were activated by the oncogenic protein K-ras. This study provides exciting insights into how the stem cell compartment operates during both normal lung-tissue homeostasis and the development of lung cancer. The new work offers perspectives on possible therapeutic interventions to combat lung cancer.

Adenocarcinoma, Bronchiolo-Alveolar↗
PubMed2004

Stem cell: balancing aging and cancer.

Stem cells are defined by their self-renewing capacity and the ability to differentiate into one or more cell types. Stem cells can be divided, depending on their origin, into embryonic or adult. Embryonic stem cells derive from early stage embryos and can give rise to cells from all three germ layers. Adult stem cells, first identified in hematopoietic tissue, reside in a variety of adult tissues. Under normal physiologic conditions, adult stem cells are capable of differentiating into the limited cell types that comprise the particular tissue or organ. Adult stem cells are responsible for tissue renewal and exhaustion of their replicative capacity may contribute to tissue aging. Loss of unlimited proliferative capacity in some of the adult stem cells and/or their progenitors may have involved the evolutionary trade-off: senescence prevents cancer but may promote aging. Embryonic stem cells exhibit unlimited self-renewal capacity due to the expression of telomerase. Although they possess some cancer cell characteristics, embryonic stem cells exhibit a remarkable resistance to genomic instability and malignant transformation. Understanding the tumor suppressive mechanisms employed by embryonic stem cells may contribute to the development of novel cancer treatments and safe cell-based therapies for age-related diseases.

Adult↗
PubMedDate not supplied

Prostate cancer stem cells, telomerase biology, epigenetic modifiers, and molecular systemic therapy for the androgen-independent lethal phenotype.

Numerous, relatively well-characterized androgen-independent osteotropic prostate cancer cell lines are now available to interrogate clinically relevant fundamental questions of prostate cancer metastasis and lethal progression systematically. Mounting basic and translational science efforts reveal that, very likely, the currently incurable form of androgen independent osseous prostate cancer originates from a more undifferentiated or "stem cell" like component, coexisting within a heterogeneous tumor mass containing more differentiated epithelial cancer subtypes. Current therapeutic preclinical investigations point toward the use of epigenetic modifiers, such as histone deacetylase inhibitors, to abrogate the continued survival of prostate cancer cells and likely can be used relatively chronically, with little morbidity. Telomere maintenance is critical in the immortalization of prostate cancer cells, and all known androgen independent cell line variants invariably express telomerase, and, thus, an argument can be made that these aggressive cells are likened to immature, progenitor variants. The arena of telomere biology has evolved enough to provide precise, nontoxic small molecule inhibitors of telomerase that limit viability of androgen-independent cell lines, yielding apoptosis. Both epigenetic modifiers and telomerase-directed small molecule inhibitors have enhanced efficacy when given in combination with conventional and novel cytotoxic drugs. Better knowledge of the "stem cell" nature of prostate cancer will help direct the molecularly targeted therapies of the near future.

Androgens↗
PubMed2005

Opinion: migrating cancer stem cells - an integrated concept of malignant tumour progression.

The dissemination of tumour cells is the prerequisite of metastases and is correlated with a loss of epithelial differentiation and the acquisition of a migratory phenotype, a hallmark of malignant tumour progression. A stepwise, irreversible accumulation of genetic alterations is considered to be the responsible driving force. But strikingly, metastases of most carcinomas recapitulate the organization of their primary tumours. Although current models explain distinct and important aspects of carcinogenesis, each alone can not explain the sum of the cellular changes apparent in human cancer progression. We suggest an extended, integrated model that is consistent with all aspects of human tumour progression - the 'migrating cancer stem (MCS)-cell' concept.

Animals↗
PubMed1980

Culture of human head and neck cancer stem cells using soft agar.

The soft-agar stem-cell assay was applied to head and neck cancer. We have successfully grown 23 (64%) of 36 head and neck tumors from both primary lesions and metastases. More poorly differentiated tumors had positive cultures more frequently than well-differentiated tumors. The plating efficiency (colonies per cells in the inoculum) averaged 0.006% (range, 0.001% to 0.08%). The system allows testing and sensitivity of individual tumors to cancericidal drugs, and our initial trials using methotrexate, bleomycin sulfate, and cisplatin (cisplatinum) show a high degree of variability between individual tumors.

Agar↗
PubMed2006

Telomeres and telomerase in cancer stem cells.

Alterations in telomere dynamics both suppress and facilitate malignant transformation by regulating genomic stability and cell lifespan. Checkpoints induced by telomere dysfunction play a major role in tumour suppression, whereas telomere shortening contributes to the initiation of cancer by inducing chromosomal instability. Since stem cells are exposed to various tumourigenic agents and stresses throughout their lifetime, the ageing stem cell is a major target of malignant transformation. This review summarises our knowledge of telomere length and telomerase activity in stem cells during ageing and carcinogenesis.

Cell Transformation, Neoplastic↗
PubMed1999

Adenovirus p53 purging for human breast cancer stem cell products.

Tumor cell (TC) contamination of stem cell products can contribute to relapse after high dose chemotherapy and stem cell rescue. A new purging technology using replication-deficient recombinant adenovirus (Adv) containing the p53 tumor suppressor gene (Adv-p53) has been suggested to reduce tumor contamination of autologous stem cell product. We demonstrate herein a safe and effective Adv-p53 purging procedure using four human breast cancer TC lines. Multiple parameters need to be achieved to successfully purge stem cell products, including a high cell:virus ratio, a small incubation volume, a long incubation time and 37 degrees C rather than room temperature. These parameters are all interrelated and equally important for the inhibition of TC clonogenic growth. In our studies, we also observed that Adv could nonspecifically inhibit TC clonogenic growth, although Adv-p53 treatment led to a significantly greater inhibition of clonogenic growth by cells expressing mutated p53. The presence of peripheral stem cell (PSC) products was found to decrease the effect of Adv-p53 on TC clonogenic growth, suggesting that PSC products could compete with TC for infection by recombinant Adv. However, X-Gal staining after incubation with Adv containing-galactosidase demonstrated that PSC products were 2, 000-fold more resistant to Adv infection than TC. We conclude that a 4-hour incubation of stem cell products (2 x 10(8)/ml) with 4 x 10(11) Adv-p53 particles is sufficient to completely purge TC with no effect on hematopoietic cell function.

Adenoviridae↗
PubMed2006

Stem cells in prostate cancer: resolving the castrate-resistant conundrum and implications for hormonal therapy.

Androgen deprivation therapy (ADT) is initial systemic therapy for advanced prostate cancer and is used as an adjuvant to local therapy for high-risk disease, but responses in advanced disease are transient. Prostate cancer stem cells are a small fraction of tumor cells that give rise to malignant cells. Initial or acquired stem cell resistance to castration must therefore underlie castrate-resistant prostate cancer. We sought to review the evidence on cancer stem cells and androgen deprivation therapy to determine if prostate cancer stem cell resistance occurs from the outset, or if it is an acquired resistance. Prostate cancer stem cells do not express androgen receptor (AR) and hence should not be directly responsive to androgen deprivation therapy. However, castrate-resistant tumors that are derived from stem cells, have molecular changes such as amplification of the androgen receptor gene, or other genetic changes resulting in gain-of-function changes in AR, implying an acquired resistance to androgen deprivation. The origins of castrate-resistant tumors, with mechanisms such as androgen receptor gene amplification from androgen receptor negative prostate cancer stem cells, is an apparent conundrum. Insight into how this occurs may lead to new treatments that overcome or delay castrate-resistance. Herein, we review the evidence on cancer stem cells, the benefits of ADT, the biological basis of response to ADT, and mechanisms of castrate-resistance. We also explore the apparent conundrum of why AR-negative prostate cancer stem cells can give rise to castrate-resistant prostate cancer. We propose possible explanations that may resolve this conundrum and discuss implications for hormonal therapy.

Androgen Antagonists↗
PubMed2006

Pten dependence distinguishes haematopoietic stem cells from leukaemia-initiating cells.

Recent advances have highlighted extensive phenotypic and functional similarities between normal stem cells and cancer stem cells. This raises the question of whether disease therapies can be developed that eliminate cancer stem cells without eliminating normal stem cells. Here we address this issue by conditionally deleting the Pten tumour suppressor gene in adult haematopoietic cells. This led to myeloproliferative disease within days and transplantable leukaemias within weeks. Pten deletion also promoted haematopoietic stem cell (HSC) proliferation. However, this led to HSC depletion via a cell-autonomous mechanism, preventing these cells from stably reconstituting irradiated mice. In contrast to leukaemia-initiating cells, HSCs were therefore unable to maintain themselves without Pten. These effects were mostly mediated by mTOR as they were inhibited by rapamycin. Rapamycin not only depleted leukaemia-initiating cells but also restored normal HSC function. Mechanistic differences between normal stem cells and cancer stem cells can thus be targeted to deplete cancer stem cells without damaging normal stem cells.

Animals↗
PubMed2005

Stem cells and brain cancer.

One of the most devastating CNS pathologies is brain cancer. The undifferentiated character of brain tumor cells and recent reports of cancer stem cells prompt questions regarding the involvement of normal stem/progenitor cells in brain tumor biology, their potential contribution to the tumor itself, and whether they are the cause or the consequence of tumor initiation and progression. The cancer stem cell model proposes a clonally derived brain tumor arising from a cancer stem cell. This tumor cell-of-origin originates from a stem/progenitor or more differentiated cell via acquisition of oncogenic mutations that dysregulate or allow reacquisition of self-renewal mechanisms. The tumor cells differentiate unidirectionally from the cancer stem cell in a way parallel to normal development. However, several properties of brain tumors add complexity to this model. For example, the apparent lineage and differentiation status of tumor cells are significantly affected by signaling abnormalities that are causally related to formation of the tumor. In addition, these tumors recruit normal CNS stem and progenitor cells to the tumor mass leading to the possibility of a heterogeneous and polyclonal cell population. It is likely that a complete description of the role of stem cells in brain tumors will be more complex than our current models.

Animals↗
PubMed2006

A human colon cancer cell capable of initiating tumour growth in immunodeficient mice.

Colon cancer is one of the best-understood neoplasms from a genetic perspective, yet it remains the second most common cause of cancer-related death, indicating that some of its cancer cells are not eradicated by current therapies. What has yet to be established is whether every colon cancer cell possesses the potential to initiate and sustain tumour growth, or whether the tumour is hierarchically organized so that only a subset of cells--cancer stem cells--possess such potential. Here we use renal capsule transplantation in immunodeficient NOD/SCID mice to identify a human colon cancer-initiating cell (CC-IC). Purification experiments established that all CC-ICs were CD133+; the CD133- cells that comprised the majority of the tumour were unable to initiate tumour growth. We calculated by limiting dilution analysis that there was one CC-IC in 5.7 x 10(4) unfractionated tumour cells, whereas there was one CC-IC in 262 CD133+ cells, representing >200-fold enrichment. CC-ICs within the CD133+ population were able to maintain themselves as well as differentiate and re-establish tumour heterogeneity upon serial transplantation. The identification of colon cancer stem cells that are distinct from the bulk tumour cells provides strong support for the hierarchical organization of human colon cancer, and their existence suggests that for therapeutic strategies to be effective, they must target the cancer stem cells.

AC133 Antigen↗
PubMed2006

Stem cells and cancer: an intimate relationship.

Tumour-wide 'omics' approaches have long held sway as the approach to identifying useful therapeutic targets. This view is changing with the realization that many, if not all, cancers contain a minority population of self-renewing stem cells, the cancer stem cells, which are entirely responsible for sustaining the tumour as well as giving rise to proliferating but progressively differentiating cells that are responsible for much of the cellular heterogeneity that is so familiar to histopathologists. Moreover, although many tumours probably have their origins in normal stem cells, persuasive evidence from the haematopoietic system suggests that genetic alterations in more committed progenitor cells can reactivate the self-renewal machinery, resulting in a further source of cancer stem cells. Thus, the bulk of the tumour is not the problem, and so the identification of cancer stem cells and the factors that regulate their behaviour are likely to have an enormous bearing on the way that we treat neoplastic disease in the future.

Bone Marrow Cells↗