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Centre for Urological Research, Monash Institute of Medical Research, Monash University, Clayton, Victoria 3168, Australia
Address all correspondence and requests for reprints to: Gail P. Risbridger, Centre for Urological Research, Monash Institute of Medical Research, Monash University, 27–31 Wright Street, Clayton, Victoria 3168, Australia. E-mail: gail.risbridger{at}med.monash.edu.au.
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Abstract |
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PROSTATE CANCER (PCa) is an endocrine-related disease and is hormonally regulated. Androgen deprivation has been an effective treatment for PCa because it initiates epithelial cell apoptosis. However, the use of androgen withdrawal/ablation as the front-line therapy for prostate disease has two main drawbacks: firstly, after initial remission, recurrent disease becomes androgen independent and unable to be cured (1). Secondly, androgen withdrawal has adverse effects on bone, muscle, and cognitive function in aged men (2). The recurrence of androgen-independent PCa is thought to occur because prostatic stem cells, resistant to androgen deprivation, resume their growth despite androgen ablation. Many laboratories have sought to isolate prostatic stem cells to understand the processes that govern their hormone-dependent and -independent growth and differentiation and ultimately lead to the development of new therapies for PCa.
Despite the best efforts of researchers in this field, prostatic epithelial stem cells have not been definitively identified or characterized at the single cell level. Enriched populations of stem/progenitor cells have been described in both mouse and human prostates that have self-renewal and regenerative capacity. In the mouse, a number of molecular markers of stem cell have been proposed, including Sca1 and CD49f (3). Although the location of these cells is not clear, the basal cell layer is thought to house the putative stem cells, but this fact remains in contention (4). Basal cells marked by p63 are believed to regulate commitment to the prostatic lineage (5), however, when the prostatic anlagen was rescued from p63 null mice that die at birth, the complete prostatic cell lineage was regenerated (6). In the human, the situation is similar; the exact identity and location of the stem cell remains to be defined. The most enriched population was described by the Maitland laboratory where Collins and et al. (7, 8) described the use of cell surface markers 
2β1 integrin in conjunction with CD133 to isolate prostatic stem cells from normal and cancer specimens The general consensus is that putative prostatic stem cells are devoid of androgen receptors (ARs) (9) and epithelial differentiation is regulated indirectly via stromal androgen stimulation (10). Fibroblast growth factors (especially FGF-7 and FGF-10) are key stromal-derived growth factors regulating these paracrine interactions in normal and malignant pathologies (11, 12).
In the absence of tools to mark and investigate the regulation of putative stem cells at single-cell resolution, alternate approaches are required to address their functional biology. The approaches reviewed in this article revolve around the role of the stromal cell niche. Although stem cells possess internal cell signaling machinery, it is well recognized that the stem cell microenvironment, determined partly by the surrounding tissue stroma, defines the stem cell niche and directs stem cell fate [reviewed in Morrison and Spradling (13)].
Pivotal to this approach is the use of tissue recombination. Epithelia containing the putative stem cells can be isolated and recombined with stroma different to those that normally surround the epithelia in vivo. In this way, it is possible to expose the stem cells to different stromal microenvironments and test the resultant effect on stem cell growth and differentiation. Thus, normally growth quiescent adult tissue can be stimulated by the microenvironment provided by embryonic prostatic stroma or urogenital mesenchyme (UGM) to regenerate prostatic ductal structures lined by epithelia containing all mature epithelial cell types (14, 15). The power of the murine mesenchyme is such that is can redirect the differentiation of mouse bladder epithelia to generate prostatic ductal structures (16). In addition, rat UGM can induce human prostatic epithelia to form prostatic ducts lined by human epithelia (17). These data showed that stromal-epithelial cell signaling is a reciprocal event, conserved across species, providing us with the means to make human rodent chimeras to test human and mouse stem cell differentiation. The underlying mechanisms of action remain to be fully elucidated but activation of a series of transcription factors is necessary, including Foxa1, Nkx3.1, and AR (18, 19).
The advent of stem cell technology has provided new avenues to investigate the processes governing stem cell differentiation and growth by the stroma, and the first set of data for review support the notion that the stromal microenvironment or niche directs stem cell fate. Because there is species conservation in stromal signaling to epithelia, and stroma can determine the fate of committed epithelial cells, several laboratories sought to determine whether the stroma could direct uncommitted pluripotent stem cells. In our own studies, human embryonic stem (ES) cells were recombined with rat or mouse prostatic mesenchyme, resulting in the generation of human prostatic tissues composed of all epithelial cells types and secreting prostatic-specific antigen, a human-specific marker of differentiation and maturation (20). Subsequently, murine ES cells were used to generate bladder tissue when recombined with bladder stroma (21) and pancreas using embryonic tissues (22). Thus, the principle that the embryonic stroma directs pluripotent stem cell fate was proven by an independent set of investigators working in another tissue (Figure 1
).
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In malignancy, as in healthy tissue, the role of the stroma has been actively investigated by pathologists and biologists, particularly in endocrine-related cancers. Extending the observation that human and murine tissues use conserved signaling mechanisms, Hayward et al. (23) showed that the progression of malignancy was regulated by the stromal cell niche. Human epithelial cells derived from a man with BPH (BPH-1) were immortalized with simian virus 40T antigen and used as a source of epithelia, but because BPH-1 cells are karyotypically abnormal and do not express AR, these cells are recognized as abnormal and designated as "initiated" epithelia. Despite these lesions and genetic abnormality, the BPH-1 cells are nontumorigenic; but, when recombined with tumor stroma or cancer-associated fibroblasts (CAFs) from men with PCa, BPH-1 cells form tumors (24). Similar findings were demonstrated using a different nontumorigenic epithelial cell line, NbE-I, which formed malignant tumors when coinoculated with tumorigenic rat UGM (25). Thus, tumor stroma, but not nonmalignant stroma, promotes tumor progression in initiated prostatic epithelia. Genetic analysis of CAFs revealed several key candidates involved in this process, including secreted frizzled-related protein 1 (SFRP1), TGF-β1 (TGF-β1), and stromal cell-derived factor-1 (SDF-1/CXCL12) (26, 27). Whether tumor stroma or CAFs initiate malignancy in normal epithelial cells remains an important question because it will define the need to identify the stroma as a primary therapeutic target for cancer.
Tumor stroma is recognized by its pathology and molecular signature (27) but regarded as a passive player in tumorigenesis, reacting to the changes originating in the adjacent epithelia (24). To test whether tumor stroma can provide a different niche for stem cells, we recombined human ES cells with CAFs. When grafted into the kidney capsule of host mice, human ES cells form teratomas that rapidly enlarge and kill the host. When recombined with CAFs, the teratoma formation is significantly abrogated, demonstrating that the stromal niche is able to influence human ES cell differentiation. Furthermore, the CAF-derived niche differs from that derived from nonmalignant prostatic fibroblasts that were unable to alter or impede teratoma formation (Figure 2). Despite these observations, the quest to show that a CAF-derived niche can initiate tumors in normal epithelia, remains unproven because few prostatic ductal structures were generated and no tumor cells were identified. Continued effort is required to generate mature epithelia and use these in recombination with CAFs to verify or reject the postulate that tumor stroma may play a key role in tumor initiation and a therapeutic target for drug development.
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Recent studies addressed whether testicular cells alter their cell fate upon interaction with the mammary gland environment, providing evidence of transdifferentiation. When dispersed spermatagonial cells (which contained active stem/progenitor cells), together with mammary epithelial cells, were transplanted into cleared mammary fat pads, mammary outgrowths were detected that were derived from the testicular cells (28). These data provide evidence for dominance of the tissue microenvironment over the intrinsic nature of stem cells. However, the exact components of the microenvironment that were critical in dictating epithelial cell fate remains unknown because these studies involved mammary stroma, including both stromal and adipose tissue, as well as mammary epithelial cells that may also act as signaling components that support glandular regeneration.
The two tissue types used in the study mentioned above were from ectoderm-derived tissues. An alternative approach to test the plasticity of stem cells across germ lineages (endoderm and ectoderm) would be to use tissue recombination with UGM as a substitute microenvironment for the transdifferentiation of adult stem cells, such as mammary stem cells. UGM has been used successfully to support the survival and promote prostatic morphogenesis of human and rodent adult epithelial cells of endoderm-derived tissues, and these studies should be reevaluated with isolated stem cell populations of other germ lineages. One would predict that stem cells would change their differentiation fate and generate altered epithelial progeny. Whether they fully commit to the new lineage, or retain some intrinsic properties, remains to be determined and will have significant implications for the field of tissue regeneration. These studies would also exemplify the extent of adult stem cell plasticity across germ lineages.
In summary, this review has evaluated the evidence that the stromal cell niche plays a key role in defining the stem cell niche and directing stem cell fate. Firstly, stromal-epithelial stem cell signaling is conserved across species, making it possible to use rodent stroma to direct the fate of human stem cells, and exemplified by the generation of human prostatic epithelia from pluripotent human ES cells. Secondly, malignant tumor stroma abrogates teratoma formation, but there is little evidence that tumor stroma initiates tumor formation, although it is known to promote tumor progression. Finally reprogramming of adult stem cells by alteration of the stromal cell niche resulting in transdifferentiation would provide novel evidence of the full potential of the stroma to direct and redirect stem cell fate. The significance of all these studies relates to tissue regeneration. Whether stem cells are successful or not in generating new organs and tissue will largely depend on their location, determined by the surrounding stroma. As the real estate agent would say to the home buyer, "It is all about the location, location, location."
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Acknowledgments |
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Footnotes |
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Author Disclosure Summary: The authors have nothing to disclose.
First Published Online June 5, 2008
Abbreviations: AR, Androgen receptor; BPH, benign prostatic hyperplasia; ES, embryonic stem; FGF, fibroblast growth factor; PCa, prostate cancer; UGM, urogenital mesenchyme.
Received April 2, 2008.
Accepted for publication May 27, 2008.
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(2)β(1)-integrin expression. J Cell Sci 114:3865–3872
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