The role of microRNAs in prostate cancer migration,invasion, and metastasis

Prostate cancer (PCa) is considered the most prevalent malignancy and the second major cause of cancer-related death in males from Western countries. PCa exhibits variable clinical pictures, ranging from dormant to highly metastatic cancer. PCa suffers from poor prognosis and diagnosis markers, and novel biomarkers are required to define disease stages and to design appropriate therapeutic approach by considering the possible genomic and epigenomic differences. MicroRNAs (miRNAs) comprise a class of small noncoding RNAs, which have remarkable functions in cell formation, differentiation, and cancer development and contribute in these processes through controlling the expressions of protein-coding genes by repressing translation or breaking down the messenger RNA in a sequence-specific method. miRNAs in cancer are able to reflect informative data about the current status of disease and this might benefit PCa prognosis and diagnosis since that is concerned to PCa patients and we intend to highlight it in this paper.     

CDKN1B Val 109 Gly variant is not related to risk of prostate cancer

Association between CDKN1B gene Val 109 Gly polymorphism and prostate cancer (PCa) susceptibility has been investigated in several studies but with inconsistent conclusions. We adopted odds ratios (ORs) and 95% confidence intervals (CIs) to assess the correlation between CDKN1B Val 109 Gly variant and PCa susceptibility. Moreover, we used in-silico tools to evaluate the relationship of CDKN1B expression and overall survival (OS) or disease free survival (DFS) time in PCa patients. The overall results demonstrated no association of the CDKN1B variant on PCa risk [allelic contrast (OR = 0.78, 95% CI = 0.45 − 1.35, P_{heterogeneity} = 0.038); GV vs VV (OR = 0.83, 95% CI = 0.56 − 1.25, P_{heterogeneity} = 0.253); GG vs VV (OR = 0.48, 95% CI = 0.23 − 1.01, P_{heterogeneity} = 0.161); GG+GV vs VV (OR = 0.75, 95% CI = 0.52 −1.08, P_{heterogeneity} = 0.132) and GG vs GV+VV (OR = 0.63, 95% CI = 0.25 − 1.11, P_{heterogeneity} = 0.152)]. In subgroup analysis by ethnicity and source of control, we also identified similar results. In-silico results showed that expression of CDKN1B was decreased in PCa tissue, especially in less advanced PCa (Gleason score = 6 or 7). No significant difference of OS or DFS time was indicated between the low and high expression of CDKN1B. Our present study showed evidence that CDKN1B Val 109 Gly variant is not related to PCa risk. Future studies with large sample size are needed to confirm this correlation in more details.     

Hepatocyte growth factor supports androgen stimulation of growth of mouse ventral prostate epithelial cells in collagen gel matrix culture

To assess the role of hepatocyte growth factor (HGF) and androgen in growth of prostate epithelial cells, we isolated mouse ventral prostate epithelial cells and cultured them in a three-dimensional type I collagen gel matrix under serum-free conditions. Although the prostate epithelial cells tended to die in the insulin-supplemented basal medium, 5alpha-dihydrotestosterone (DHT) prevented the cell death, and HGF slightly stimulated the growth. By contrast, coexistence of DHT and HGF greatly augmented the growth and branching morphogenesis of the epithelial cells. Some of the outgrowths formed under these conditions showed enlarged structures resembling the prostate ducts or alveoli. Examination of the stromal cell-conditioned medium revealed that a growth-stimulating activity is present in the conditioned medium. A major portion of this activity was abolished by anti-HGF IgG. These observations suggest that HGF is produced by the stromal cells of the prostate gland and supports the androgen stimulation of growth of the epithelial cells.     

Human DU145 prostate cancer cells overexpressing mitogen-activated protein kinase phosphatase-1 are resistant to Fas ligand-induced mitochondrial perturbations and cellular apoptosis

Recent studies have suggested that MAP kinase phosphatase 1 (MKP-1) is overexpressed in prostate cancer. To evaluate the role of MKP-1 in regulating cell death and tumor growth in prostate cancer, MKP-1 was conditionally overexpressed in the human prostate cancer cell line DU145. Overexpression of MKP-1 in DU145 cells blocked activation of stress-activated protein kinase (SAPK/JNK). MKP-1 overexpression in DU-145 cells was also found to inhibit Fas ligand (FasL)-induced apoptosis, as well as block the activation of caspases by Fas engagement. In addition, MKP-1 blocked the activation of apoptosis by transfected MEKK-1 and ASK-1, presumably through its inhibition of the SAPK/JNK family of enzymes. MKP-1 blocked the ability of FasL to induce loss of mitochondrial transmembrane potential (_m), suggesting that MKP-1 acts upstream of mitochondrial pro-apoptotic events induced by FasL and that the SAPK/JNK pathway may form the signaling link between Fas receptor and mitochondrial dysfunction. Thus, MKP-1 overexpression in prostate cancer may play a role in promoting prostate carcinogenesis by inhibiting FasL-induced cell death.     

Dynamic process of prostate cancer metastasis to bone

Prostate cancer metastasis to the bone occurs at high frequency in patients with advanced disease, causing significant morbidity and mortality. Over a century ago, the "seed and soil" theory was proposed to explain organ-specific patterns of metastases. Today, this theory continues to be relevant as we continue to discover factors involved in the attraction and subsequent growth of prostate cancer cells to the bone. These include the accumulation of genetic changes within cancer cells, the preferential binding of cancer cells to bone marrow endothelial cells, and the release of cancer cell chemoattractants from bone elements. A key mediator throughout this metastatic process is the integrin family of proteins. Alterations in integrin expression and function promote dissociation of cancer cells from the primary tumor mass and migration into the blood stream. Once in circulation, integrins facilitate cancer cell survival through interactions between other cancer cells, platelets, and endothelial cells of the target bone. Furthermore, dynamic changes in integrins and in integrin-associated signal transduction aid in the extravasation of cancer cells into the bone and in expansion to a clinically relevant metastasis. Thus, we will review the critical roles of integrins in the process of prostate cancer bone metastasis, from the escape of cancer cells from the primary tumor, to their survival in the harsh "third microenvironment" of the circulation, and ultimately to their attachment and growth at distant bone sites.     

Approaches to understanding the importance and clinical implications of peroxisome proliferator-activated receptor gamma (PPARgamma) signaling in prostate cancer

The development and maintenance of the prostate are dependent upon a complex series of interactions occurring between the epithelial and stromal tissues (Hayward and Cunha [2000]: Radiol. Clin. N. Am. 38:1-14). During the process of prostatic carcinogenesis, there are progressive changes in the interactions of the nascent tumor with its surrounding stroma and extracellular matrix. These include the development of a reactive stromal phenotype and the possible promotion, by stromal cells, of epithelial proliferation and loss of differentiated function (Hayward et al. [1996]: Ann. N. Y. Acad. Sci. 784:50-62; Grossfeld et al. [1998]: Endocr. Related Cancer 5:253-270; Rowley [1998]: Cancer Metastasis Rev. 17:411-419; Tuxhorn et al. [2002]: Clin. Cancer Res. 8:2912-2923). Many molecules play an as yet poorly defined role in establishing and maintaining a growth quiescent glandular structure in the adult. Peroxisome proliferator-activated receptor gamma (PPARgamma) is a candidate regulator of prostatic epithelial differentiation and may play a role in restricting epithelial proliferation. PPARgamma agonists are relatively non-toxic and have been used with limited success to treat some prostate cancer patients. We would propose that a more complete understanding of PPARgamma biology, particularly in the context of appropriate stromal-epithelial and host-tumor interactions would allow for the selection of patients most likely to benefit from this line of therapy. In particular, it seems reasonable to suggest that the patients most likely to benefit may be those with relatively indolent low stage disease for whom this line of therapy could be a useful additive to watchful waiting.     

Prostate cancer association studies: pitfalls and solutions to cancer misclassification in the PSA era

Widespread screening of American men for elevated PSA has changed the characteristics of prostate cancer cases in the U.S. The influence of the changed nature of prostate cancer cases in the PSA era and the need for careful consideration of who is a "case" and who is a "control" on the ability to detect associations of risk factors with prostate cancer in etiologic epidemiologic studies merits discussion. Issue 1: prostate cancer cases diagnosed in the PSA era are enriched with a pool of early lesions, which may differ in etiology, and are deficient in advanced lesions, which are the most likely to be the product of promotion and progression events. By admixing the two types of cases (i.e., imperfect specificity), the associations previously detected using epidemiologic designs when the majority of cases were clinically detected may no longer be apparent in the PSA era when the majority of cases are now detected in the pre-clinical phase. Researchers must now tailor hypotheses such that they are testable using early stage cases or specifically augment the number of advanced cases when testing hypotheses related to extraprostatic growth and progression. Issue 2: even when controls are screened for elevated PSA to rule out the presence of prostate cancer, some proportion of those controls currently will have one or more foci of prostate cancer. The imperfect sensitivity of the PSA test coupled with diagnostic work-up may in part result from (a) lack of PSA elevation in some men with prostate cancer or (b) failure of biopsy to sample the tumor focus in men with elevated PSA. Misclassification of men with undetected prostate cancer as controls usually produces a bias that tends to deflate associations. Given this type of disease misclassification, whether an association still can be statistically detected depends on the extent of misclassification, the magnitude of the true association, the prevalence of the exposure in the true controls, and the sample size, although in general moderate nondifferential misclassification does not lead to profound attenuation. However, under the same scenario attenuation does not occur in cohort or case-cohort studies in which the rate or risk ratio (RR) is calculated. That prostate cancer cases diagnosed in the PSA era are enriched with early stage, minimally invasive disease in our opinion is likely to pose a far more serious obstacle to epidemiologic research on the etiology of clinically important prostate cancer than the issue of inclusion as controls some men who have undiagnosed prostate cancer because of imperfect sensitivity of PSA screening and biopsy sampling error.