Development Of Prostate Cancer Metastasis Research Articles

Development of a Longitudinal Prostate Cancer Transcriptomic and Clinical Data Linkage

Although tissue-based gene expression testing has become widely used for prostate cancer risk stratification, its prognostic performance in the setting of clinical care is not well understood. To develop a linkage between a prostate genomic classifier (GC) and clinical data across payers and sites of care in the US. In this cohort study, clinical and transcriptomic data from clinical use of a prostate GC between 2016 and 2022 were linked with data aggregated from insurance claims, pharmacy records, and electronic health record (EHR) data. Participants were anonymously linked between datasets by deterministic methods through a deidentification engine using encrypted tokens. Algorithms were developed and refined for identifying prostate cancer diagnoses, treatment timing, and clinical outcomes using diagnosis codes, Common Procedural Terminology codes, pharmacy codes, Systematized Medical Nomenclature for Medicine clinical terms, and unstructured text in the EHR. Data analysis was performed from January 2023 to January 2024. Diagnosis of prostate cancer. The primary outcomes were biochemical recurrence and development of prostate cancer metastases after diagnosis or radical prostatectomy (RP). The sensitivity of the linkage and identification algorithms for clinical and administrative data were calculated relative to clinical and pathological information obtained during the GC testing process as the reference standard. A total of 92 976 of 95 578 (97.2%) participants who underwent prostate GC testing were successfully linked to administrative and clinical data, including 53 871 who underwent biopsy testing and 39 105 who underwent RP testing. The median (IQR) age at GC testing was 66.4 (61.0-71.0) years. The sensitivity of the EHR linkage data for prostate cancer diagnoses was 85.0% (95% CI, 84.7%-85.2%), including 80.8% (95% CI, 80.4%-81.1%) for biopsy-tested participants and 90.8% (95% CI, 90.5%-91.0%) for RP-tested participants. Year of treatment was concordant in 97.9% (95% CI, 97.7%-98.1%) of those undergoing GC testing at RP, and 86.0% (95% CI, 85.6%-86.4%) among participants undergoing biopsy testing. The sensitivity of the linkage was 48.6% (95% CI, 48.1%-49.1%) for identifying RP and 50.1% (95% CI, 49.7%-50.5%) for identifying prostate biopsy. This study established a national-scale linkage of transcriptomic and longitudinal clinical data yielding high accuracy for identifying key clinical junctures, including diagnosis, treatment, and early cancer outcome. This resource can be leveraged to enhance understandings of disease biology, patterns of care, and treatment effectiveness.

Molecular evaluation of human papillomavirus as an oncogenic biomarker in prostate cancer.

Prostate cancer (PCa) is one of the most common tumors in men, regardless of ethnicity and demographics. In many risk factors causing PCa, genes and viral infections are strong candidates for the development of prostate tumors. Indeed, tissue infections of PCa have been reported by the presence of several types of viruses including Human Papillomaviruses (HPV). the present study was planned to determine whether HPV DNA could be detected in the blood of known men with prostate cancer and to assess the potential association between HPV infection and clinico-pathological characteristics of the patients. In order to achieve our objectives, 150 liquid blood samples were taken from Moroccan patients, 100 patients with PCa, and 50 control cases. The viral DNA was extracted, calibrated and the target genes were amplified by PCR using specific primers and the use of 2% agarose gel with visualization under UV. Of the 100 samples tested, (10%) were infected with HPV), However, none of the control cases were infected with HPV. The analysis of the data made it possible to establish a correlation between the frequency of the viral infection of the human papilloma and the tumoral criteria. Therefore, this study strengthens the potential role of HPV as a cofactor in prostate cancer development, and we propose that infection with this virus may be involved in the development of PCa metastases.

Abstract 2310: Identification of novel essential genes for prostate cancer metastasis by genome scale CRISPR approaches

Abstract Background: Thanks to the availability of new biomarkers, Prostate cancer (PCa) can now be diagnosed earlier and, as a result, PCa patients have a high 5-year survival rate. Nonetheless, the situation changes completely for patients who develop metastasis, for whom 5-year survival rate decreases to 29%. Recent candidate-gene approaches have identified new candidates, but there are still no drugs to prevent or cure metastatic PCa. Hence, there is an urgent need to find effective therapeutic targets. Methodology: In this study we have conducted a high-throughput CRISPR/Cas9 screening in highly metastatic PCa cell lines PC3 and DU145, using the CRISPR/Cas9 knock-out (GeCKO) library, that targets 18,080 genes with 64,751 unique gRNAs. To assess whether each gene loss-of-function may be critical for metastasis development, invasion assays in Matrigel-coated Boyden Chamber membranes were used. Next-generation sequencing and bioinformatic MaGECK analysis were then carried out to identify novel key genes in the development of PCa metastasis. siRNA approach was used to further validate the best candidates. Results: We found 29 candidates and several signaling pathways capable of significatively impair the invasion of, both, PC3 and DU145 cell lines when knocked-out, being PRMT7 the strongest regulator. PRMT7 gene encodes a type II methyltransferase involved in several cellular processes such as mRNA splicing or DNA repair. There are evidences that indicate it regulates EMT through methylation of E-cadherin promoter and other targets. Moreover, its overexpression correlates with higher levels of expression of MMP9 and MMP2 that lead to metastasis appearance in other types of tumors. Our results inhibiting PRMT7 expression with siRNA validated our high-throughput CRISPR/Cas9 screening results and confirmed the implication of PRMT7 in PCa invasion. Conclusions: We have conducted a novel high-throughput CRISPR-Cas9 screening, finding promising gene candidates, such as PRMT7, which, in the future could be used as therapeutical targets to prevent metastasis development in PCa patients. Furthermore, in this study we have also found genes that had been previously associated to PCa metastasis in other candidate-gene studies, giving a proof-of-concept for the use of high performance of CRISPR-Cas9 screenings for the search of candidate genes involved in PCa metastasis. Citation Format: Maria Rodrigo Faus, Sara Manzano Figueroa, Jingchun Qu, Huiqi Qu, Renata Pellegrino, Hakon Hakonarson, Paloma Bragado, Almudena Porras, Alvaro Gutierrez-Uzquiza. Identification of novel essential genes for prostate cancer metastasis by genome scale CRISPR approaches [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2310.

Human papillomavirus and prostate cancer: The role of viral expressed proteins in the inhibition of anoikis and induction of metastasis

BackgroundThe aim of this study is to address the role of HPV in prostate cancer (PCa) development through the inducement of resistance to anoikis. MethodsIn this case-control study, prostate tissues and blood samples were collected from 116 individuals, including 72 cases with PCa and 44 non‐malignant prostate tissue samples as a control group. The expression level of HPV genes (E2, E6, and E7) and cellular genes including anti-apoptotic mediators (Bcl-2 and survivin), tumor suppressor proteins (Rb and p53), and some mediators involved in anoikis resistance and invasiveness (E-cadherin, N-cadherin, Twist, PTPN13 and SLUG) were evaluated. ResultsHPV genome was identified in 36.1% cases and 15.9% control samples, additionally there was found to be a statistic significant association between the presence of HPV and PCa (OR = 1.64, 95% C.I = 0.8–1.8, P-value = 0.023). HPV genotype 16 and 18 were the most prevalent genotype in both in the PCa group and the control group. The expression level of the tumor suppressor proteins (Rb and p53) and anti-apoptotic mediators (Bcl-2 and Survivin) were significantly decreased and increased, respectively, in the HPV-positive specimens compared to the HPV-negative specimens. Furthermore, the mean expression level of N-cadherin, SLUG, and TWIST in the HPV-positive specimens was higher than HPV-negative specimens while the mean expression level of PTPN-13 and E-cadherin genes in the HPV-positive specimens was lower than HPV-negative specimens. ConclusionOur study suggests that HPV infection may be involved in the development of PCa metastases by modulating anoikis resistance related genes.

Targeting protein geranylgeranylation slows tumor development in a murine model of prostate cancer metastasis

ABSTRACTThe isoprenoid biosynthetic pathway (IBP) plays a critical role in providing substrates and enzymes necessary for the post-translational modification and thus activation of a number of proteins involved in prostate cancer metastasis. Previous work by our lab found novel compound disodium [(6Z,11E,15E)-9-[bis(sodiooxy)phosphoryl]−17-hydroxy-2,6,12,16-tetramethyheptadeca-2,6,11,15-tetraen-9-yl]phosphonate (GGOHBP), which inhibits the IBP enzyme geranylgeranyl diphosphate synthase (GGDPS), reduced protein geranylgeranylation without altering protein farnesylation. This activity significantly reduced adrenal gland tumor burden in a murine model of human prostate cancer metastasis which relied on treatment of established disease. The present study determined the ability of GGDPS inhibition to slow the development of prostate cancer metastasis in a preventative murine model. Using tail vein injection of human derived PC-3 prostate cancer cells 4 d after initiating daily GGOHBP or vehicle treatments, we found GGOHBP significantly reduced whole body tumor burden, significantly slowed the development of tumors, and prolonged overall survival as compared to vehicle treated animals. The observed reduction in soft tissue tumor burden corresponded to a biochemical reduction in Rap1A geranylgeranylation, which for prostate cancer is important in its own merit and which serves as a surrogate marker for Rho family, i.e. Rac, protein modification. This effect was present in all treated mice pointing to strong target engagement, which was not observed in non-tumor burdened tissues or control mice. Our findings reiterate a role for protein geranylgeranylation in the development of prostate cancer metastasis in vivo.

Restoring TGFβ1 pathway-related microRNAs: possible impact in metastatic prostate cancer development.

In developed countries, prostate cancer (PC) is the neoplasia more frequently diagnosed in men. The signaling pathway induced by the transforming growth factor β1 (TGFβ1) has an important role in cell growth, differentiation, and development, the downregulation of this pathway being associated with cancer development. In PC, the activation of this signaling pathway is lost, resulting in favoring of tumor growth, proliferation, and evasion of apoptosis. Several studies have shown that microRNAs (miRNAs), small non-coding RNA, are closely associated with the development, invasion, and metastasis, suggesting that they have a critical role in cancer development. Recently, Smad proteins, the signal transducers of the TGFβ1 signaling pathway, were found to regulate miRNA expression, through both transcriptional and posttranscriptional mechanisms. In this review, we summarize the mechanisms underlying Smad-mediated regulation of miRNA biogenesis and the effects on cancer development, particularly in PC. We identify that TGFβ1-related miR-143, miR-145, miR-146a, and miR-199a may have a key role in the development of prostate cancer metastasis and the restoration of their expression may be a promising therapeutic strategy for PC treatment.

Tumor Angiogenesis as an Early Marker of Long-Term Prostate Cancer Mortality

Evaluation of: Mucci LA, Powolny A, Giovannucci E et al.: Prospective study of prostate tumor angiogenesis and cancer-specific mortality in the health professionals follow-up study. J. Clin. Oncol. 27, 5627–5633 (2009). Most prostate cancer patients are diagnosed with localized disease. Long-term prostate cancer mortality is low, and many patients have been overtreated. Better prediction tools are needed to distinguish clinically insignificant, low-risk prostate cancers from lethal diseases. Tumor microvessel density, a marker of angiogenesis, has been shown to be related to the development of prostate cancer metastasis and even mortality. Mucci et al. found that morphologic characteristics of tumor microvessels, such as vessel size and irregularity, from prostatectomy specimen may be better than microvessel density as indicators of active angiogenesis, cancer aggressiveness and metastatic potential, and potentially prostate cancer-specific mortality. Prognostic tools combining angiogenesis biomarkers and clinical features led to marked improvement in the prediction of lethal prostate cancer. If these results are confirmed with studies from prostate biopsy samples, this novel prognosis tool will be of significant importance to guide clinical decision-making for localized prostate cancer.

Ecological Therapy for Cancer: Defining Tumors Using an Ecosystem Paradigm Suggests New Opportunities for Novel Cancer Treatments

We propose that there is an opportunity to devise new cancer therapies based on the recognition that tumors have properties of ecological systems. Traditionally, localized treatment has targeted the cancer cells directly by removing them (surgery) or killing them (chemotherapy and radiation). These modes of therapy have not always been effective because many tumors recur after these therapies, either because not all of the cells are killed (local recurrence) or because the cancer cells had already escaped the primary tumor environment (distant recurrence). There has been an increasing recognition that the tumor microenvironment contains host noncancer cells in addition to cancer cells, interacting in a dynamic fashion over time. The cancer cells compete and/or cooperate with nontumor cells, and the cancer cells may compete and/or cooperate with each other. It has been demonstrated that these interactions can alter the genotype and phenotype of the host cells as well as the cancer cells. The interaction of these cancer and host cells to remodel the normal host organ microenvironment may best be conceptualized as an evolving ecosystem. In classic terms, an ecosystem describes the physical and biological components of an environment in relation to each other as a unit. Here, we review some properties of tumor microenvironments and ecological systems and indicate similarities between them. We propose that describing tumors as ecological systems defines new opportunities for novel cancer therapies and use the development of prostate cancer metastases as an example. We refer to this as "ecological therapy" for cancer.

The prognostic significance of BMP-6 signaling in prostate cancer

The importance of bone-morphogenetic proteins in prostate cancer is well recognized. Bone-morphogenetic protein-6 overexpression has been shown to increase the aggressiveness and invasiveness of prostate cancer cells. Recent studies on noggin and sclerostin, potent inhibitors of bone-morphogenetic protein signaling, have found that noggin also modifies the ability of prostate cancer cells to metastasize to bone. Taken together, these results suggest that bone-morphogenetic protein-6 signaling is important in prostate cancer progression. Our study investigated the expression of bone-morphogenetic protein-6, noggin and sclerostin in human prostate specimens (n=136) by immunohistochemical staining. We found that bone-morphogenetic protein-6 was increased (P<0.001), whereas sclerostin was decreased (P=0.004) in prostate cancer compared with nodular hyperplasia. In addition, significantly higher level of bone-morphogenetic protein-6 expression was observed in high-grade prostate cancer with Gleason score ≥7 (P=0.027). Bone-morphogenetic protein-6, noggin and sclerostin alone could not predict the development of distant metastasis in our patient cohort. However, high level of bone-morphogenetic protein-6 and low level of noggin, or high level of bone-morphogenetic protein-6 and low level of both noggin and sclerostin expression in primary prostate cancer significantly predicted development of distant metastasis. The predictive value was still valid when only high-grade prostate cancers were included or when patients with secondary lesion other than bone were excluded. Taken together, these results suggest that a high level of bone-morphogenetic protein-6 signaling, resulting from increased expression of bone-morphogenetic protein-6 and decreased expression of its inhibitors, might promote the development of prostate cancer metastases. Our results also imply the potential use of bone-morphogenetic protein-6, noggin and sclerostin expression together as a prognostic predictor for metastatic progression of prostate cancer.

Identification of tumor metastasis suppressor region on the short arm of human chromosome 20.

Acquisition of metastatic ability by prostate cancer cells is the hallmark of their lethal trait and outcome. However, the genetic alterations underlying the clinical progression and pathogenesis of prostate cancer are not well understood. Several studies involving loss of heterozygosity (LOH) and comparative genomic hybridization analysis have identified distinctively altered regions on various human chromosomes, and genomic imbalance of chromosome 20 was implicated in progression and recurrence of prostate tumors. To examine the role of chromosome 20 in prostate neoplasms, we introduced this chromosome into highly metastatic rat prostate cancer cells using the microcell-mediated chromosome transfer technique. Introduction of the chromosome resulted in significant suppression of the metastatic ability of the hybrid cells, by as much as 98%, without any interference with the in vivo growth rate or tumorigenicity of primary tumor in SCID mice. Our STS-PCR analysis on 10 hybrid clones indicates that the suppressor activity of chromosome 20 is located in the p11.23-12 region. Further examination of the hybrid clones by experimental metastasis assay and histologic analysis as well as Matrigel invasion assay suggests the involvement of the suppressor region at an early stage of invasion and extravasation. We also investigated the status of the chromosome 20 suppressor region in pathology specimens from human prostate cancer patients and detected the frequent loss of this region in high-grade tumors. These results suggest the presence of a putative suppressor gene on human chromosome 20 that is functionally involved in development of prostate cancer metastases.