Biomedical subjects

Anne T Collins

Publications and source records attributed to Anne T Collins.

4 recordsLinked to original sources

PubMed2006

Prostate cancer stem cells.

Prostate cancer is the most frequently diagnosed cancer in men. Despite recent advances in the detection of early prostate cancer there is little effective therapy for patients with locally advanced and/or metastatic disease. The majority of patients with advanced disease respond initially to androgen ablation therapy. However, most go on to develop androgen-independent tumours that inevitably are fatal. A similar response is seen to chemotherapeutic and radiotherapy treatments. As a result, metastatic prostate cancer remains an incurable disease by current treatment strategies. Recent reports of cancer stem cells have prompted questions regarding the involvement of normal stem/progenitor cells in prostate tumour biology, their potential contribution to the tumour itself and whether they are the cause of tumour initiation and progression. Although still controversial, the cancer stem cell is likely to be the most crucial target in the treatment of prostate cancer, and a thorough understanding of its biology, particularly of how the cancer stem cell differs from the normal stem cell, might allow it to be targeted selectively and eliminated, thus improving therapeutic outcome.

Cell Proliferation↗

PubMed2006

KGF suppresses alpha2beta1 integrin function and promotes differentiation of the transient amplifying population in human prostatic epithelium.

Prostate epithelial stem cells are self-renewing cells capable of differentiation into prostate epithelium, and are thought to contribute towards both benign and malignant conditions in the human prostate. We have previously demonstrated that prostate epithelial basal cells express high levels of integrin alpha2beta1 and this population can be subdivided into stem (alpha2beta1(hi) CD133+) and transient-amplifying population (TAP) cells (alpha2beta1(hi) CD133-). However, the molecular mechanism(s) controlling the commitment and regulation of these cells towards differentiated epithelium remains unclear. Here, we demonstrate that beta1 integrin function is required for the maintenance of basal prostatic epithelial cells and suppression of its function by either methylcellulose or, more specifically, beta1-blocking antibody (80 microg/ml) induces differentiation, with associated expression of the differentiation-specific markers prostate acid phosphatase (PAP) and cytokeratin 18 (CK18). Keratinocyte growth factor (KGF), a stromal-derived growth factor, has previously been implicated in prostate organogenesis using in vitro tissue recombination experiments. We show that treatment with KGF (10 ng/ml) potently induces epithelial differentiation with concomitant suppression of alpha2beta1 integrin expression as well as the induction of androgen receptor expression. Specifically, p38-MAPK appears to be involved and the presence of SB202190, a p38 inhibitor, significantly blocks KGF-induced differentiation. Furthermore, the expression of the high-affinity receptor tyrosine kinase to KGF (FGFR2) is predominantly detectable in alpha2beta1(hi) CD133- TAP cells when compared with stem cells (alpha2beta1(hi) CD133+), which would therefore be relatively unresponsive to the differentiating effect of KGF. Taken together, using a human primary culture model, we have demonstrated key roles for interactions between KGF and integrin-mediated function in the regulation of prostate epithelial differentiation.

Aged↗

PubMed2005

Prospective identification of tumorigenic prostate cancer stem cells.

Existing therapies for prostate cancer eradicates the bulk of cells within a tumor. However, most patients go on to develop androgen-independent disease that remains incurable by current treatment strategies. There is now increasing evidence in some malignancies that the tumor cells are organized as a hierarchy originating from rare stem cells that are responsible for maintaining the tumor. We report here the identification and characterization of a cancer stem cell population from human prostate tumors, which possess a significant capacity for self-renewal. These cells are also able to regenerate the phenotypically mixed populations of nonclonogenic cells, which express differentiated cell products, such as androgen receptor and prostatic acid phosphatase. The cancer stem cells have a CD44+/alpha2beta1hi/CD133+ phenotype, and we have exploited these markers to isolate cells from a series of prostate tumors with differing Gleason grade and metastatic states. Approximately 0.1% of cells in any tumor expressed this phenotype, and there was no correlation between the number of CD44+/alpha2beta1hi/CD133+ cells and tumor grade. The identification of a prostate cancer stem cell provides a powerful tool to investigate the tumorigenic process and to develop therapies targeted to the stem cell.

AC133 Antigen↗

PubMed2004

CD133, a novel marker for human prostatic epithelial stem cells.

Stem cells are clonogenic cells with self-renewal and differentiation properties, which may represent a major target for genetic damage leading to prostate cancer and benign prostatic hyperplasia. Stem cells remain poorly characterised because of the absence of specific molecular markers that permit us to distinguish them from their progeny, the transit amplifying cells, which have a more restricted proliferative potential. Human CD133 antigen, also known as AC133, was recently identified as a haematopoietic stem cell marker. Here we show that a small population (approximately 1%) of human prostate basal cells express the cell surface marker CD133 and are restricted to the alpha(2)beta(1)(hi) population, previously shown to be a marker of stem cells in prostate epithelia. alpha(2)beta(1)(hi)/CD133(+) cells exhibit two important attributes of epithelial stem cells: they possess a high in vitro proliferative potential and can reconstitute prostatic-like acini in immunocompromised male nude mice.

AC133 Antigen↗