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Transcription profiling of human prostate cancer primary cell line vs metastasis cell line reveals Protein 4.1B suppresses prostate cancer progression and metastasis

ABSTRACT: Protein 4.1B is a 4.1/ezrin/radixin/moesin (FERM) domain-containing protein whose expression is frequently lost in a variety of human tumors, including meningiomas, non-small-cell lung cancers and breast carcinomas. However, its potential tumor suppressive function under in vivo conditions remains to be validated. In a screen for genes involved with prostate cancer metastasis, we found that 4.1B expression is reduced in highly metastatic tumors. Downregulation of 4.1B increased the metastatic propensity of poorly metastatic cells in an orthotopic model of prostate cancer. Furthermore, 4.1B-deficient mice displayed increased susceptibility for developing aggressive, spontaneous prostate carcinomas. In both cases, enhanced tumor malignancy was associated with reduced apoptosis. As expression of Protein 4.1B is frequently downregulated in human clinical prostate cancer, as well as in a spectrum of other tumor types, these results suggest a more general role for Protein 4.1B as a negative regulator of cancer progression to metastatic disease. Experiment Overall Design: primary cell line vs metastasis cell line

ORGANISM(S): Homo sapiens

SUBMITTER: Wong SY

PROVIDER: S-ECPF-GEOD-7930 | biostudies-other | 2007 Jul

REPOSITORIES: biostudies-other

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Transcription profiling of human prostate cancer primary cell line vs metastasis cell line reveals Protein 4.1B suppresses prostate cancer progression and metastasis

Project description:Protein 4.1B is a 4.1/ezrin/radixin/moesin (FERM) domain-containing protein whose expression is frequently lost in a variety of human tumors, including meningiomas, non-small-cell lung cancers and breast carcinomas. However, its potential tumor suppressive function under in vivo conditions remains to be validated. In a screen for genes involved with prostate cancer metastasis, we found that 4.1B expression is reduced in highly metastatic tumors. Downregulation of 4.1B increased the metastatic propensity of poorly metastatic cells in an orthotopic model of prostate cancer. Furthermore, 4.1B-deficient mice displayed increased susceptibility for developing aggressive, spontaneous prostate carcinomas. In both cases, enhanced tumor malignancy was associated with reduced apoptosis. As expression of Protein 4.1B is frequently downregulated in human clinical prostate cancer, as well as in a spectrum of other tumor types, these results suggest a more general role for Protein 4.1B as a negative regulator of cancer progression to metastatic disease. Experiment Overall Design: primary cell line vs metastasis cell line

2008-06-15 | E-GEOD-7930 | biostudies-arrayexpress

Protein 4.1B suppresses prostate cancer progression and metastasis.

Project description:Protein 4.1B is a 4.1/ezrin/radixin/moesin domain-containing protein whose expression is frequently lost in a variety of human tumors, including meningiomas, non-small-cell lung cancers, and breast carcinomas. However, its potential tumor-suppressive function under in vivo conditions remains to be validated. In a screen for genes involved with prostate cancer metastasis, we found that 4.1B expression is reduced in highly metastatic tumors. Down-regulation of 4.1B increased the metastatic propensity of poorly metastatic cells in an orthotopic model of prostate cancer. Furthermore, 4.1B-deficient mice displayed increased susceptibility for developing aggressive, spontaneous prostate carcinomas. In both cases, enhanced tumor malignancy was associated with reduced apoptosis. Because expression of Protein 4.1B is frequently down-regulated in human clinical prostate cancer, as well as in a spectrum of other tumor types, these results suggest a more general role for Protein 4.1B as a negative regulator of cancer progression to metastatic disease.

| S-EPMC1924789 | biostudies-literature

Protein 4.1B suppresses prostate cancer progression and metastasis

2007-07-02 | GSE7930 | GEO

Stromal FOXF2 suppresses prostate cancer progression and metastasis by enhancing antitumor immunity.

Project description:Cancer-associated fibroblasts (CAFs) mediate an immunosuppressive effect, but the underlying mechanism remains incompletely defined. Here we show that increasing prostatic stromal Foxf2 suppresses the growth and progression of both syngeneic and autochthonous mouse prostate cancer models in an immunocompetent context. Mechanistically, Foxf2 moderately attenuates the CAF phenotype and transcriptionally downregulates Cxcl5, which diminish the immunosuppressive myeloid cells and enhance T cell cytotoxicity. Increasing prostatic stromal Foxf2 sensitizes prostate cancer to the immune checkpoint blockade therapies. Augmenting lung stromal Foxf2 also mediates an immunosuppressive milieu and inhibits lung colonization of prostate cancer. FOXF2 is expressed higher in the stroma of human transition zone (TZ) than peripheral zone (PZ) prostate. The stromal FOXF2 expression level in primary prostate cancers inversely correlates with the Gleason grade. Our study establishes Foxf2 as a stromal transcription factor modulating the tumor immune microenvironment and potentially explains why cancers are relatively rare and indolent in the TZ prostate.

| S-EPMC9652358 | biostudies-literature

Expression profiling of a human cell line model of prostatic cancer reveals a direct involvement of interferon signaling in prostate tumor progression.

Project description:Cancer-associated fibroblasts induce malignant behavior in genetically initiated but nontumorigenic human prostatic epithelium. The genetic basis for such transformation is still unknown. By using Affymetrix GeneChip technology, we profiled genomewide gene expression of transformed [tumorigenic benign prostatic hyperplasia (BPH1)(CAFTD)] and parental (nontumorigenic BPH1) cells. We identified differentially expressed genes, which are associated with tumorigenesis or tumor progression. One striking finding is that a significant portion of the down-regulated genes belongs to interferon (IFN)-inducible molecules. We show that IFN inhibited the tumorigenic BPH1(CAFTD) cell proliferation and colony formation in vitro and inhibited tumor growth in xenografts in vivo. Expression of the IFN-inducible molecules correlates with the growth-inhibiting effects of IFN. In addition, these genes are reported to be mapped mainly to two chromosomal regions, 10q23-26 and 17q21, which are frequently deleted in human prostate cancers. Furthermore, in silico data-mining with the GeneLogic database revealed that expression of the IFN-inducible genes was down-regulated in approximately 30% of the 49 clinically characterized samples of prostatic adenocarcinomas. Collectively, we show that there seems to be a direct link between IFN-inducible molecules and prostatic tumor progression. These findings suggest IFN-inducible molecules as potential therapeutic targets for the treatment of prostate cancer.

| S-EPMC122433 | biostudies-literature

SPARCL1 suppresses metastasis in prostate cancer.

Project description:PurposeMetastasis, the main cause of death from cancer, remains poorly understood at the molecular level.Experimental designBased on a pattern of reduced expression in human prostate cancer tissues and tumor cell lines, a candidate suppressor gene (SPARCL1) was identified. We used in vitro approaches to determine whether overexpression of SPARCL1 affects cell growth, migration, and invasiveness. We then employed xenograft mouse models to analyze the impact of SPARCL1 on prostate cancer cell growth and metastasis in vivo.ResultsSPARCL1 expression did not inhibit tumor cell proliferation in vitro. By contrast, SPARCL1 did suppress tumor cell migration and invasiveness in vitro and tumor metastatic growth in vivo, conferring improved survival in xenograft mouse models.ConclusionsWe present the first in vivo data suggesting that SPARCL1 suppresses metastasis of prostate cancer.

| S-EPMC3838491 | biostudies-literature

Endoglin suppresses human prostate cancer metastasis.

Project description:Endoglin is a transmembrane receptor that suppresses human prostate cancer (PCa) cell invasion. Small molecule therapeutics now being tested in humans can activate endoglin signaling. It is not known whether endoglin can regulate metastatic behavior, PCa tumor growth, nor what signaling pathways are linked to these processes. This study sought to investigate the effect of endoglin on these parameters. We used a murine orthotopic model of human PCa metastasis, designed by us to measure effects at early steps in the metastatic cascade, and implanted PCa cells stably engineered to express differing levels of endoglin. We now extend this model to measure cancer cells circulating in the blood. Progressive endoglin loss led to progressive increases in the number of circulating PCa cells as well as to the formation of soft tissue metastases. Endoglin was known to suppress invasion by activating the Smad1 transcription factor. We now show that it selectively activates specific Smad1-responsive genes, including JUNB, STAT1, and SOX4. Increased tumor growth and increased Ki67 expression in tissue was seen only with complete endoglin loss. By showing that endoglin increased TGFβ-mediated suppression of cell growth in vitro and TGFβ-mediated signaling in tumor tissue, loss of this growth-suppressive pathway appears to be implicated at least in part for the increased size of endoglin-deficient tumors. Endoglin is shown for the first time to suppress cell movement out of primary tumor as well as the formation of distant metastasis. It is also shown to co-regulate tumor growth and metastatic behavior in human PCa.

| S-EPMC3046557 | biostudies-literature

miR186 suppresses prostate cancer progression by targeting Twist1.

Project description:Prostate cancer (PCa) is the second leading cause of cancer-related deaths in north American men, and most its related deaths are due to advanced and metastatic PCa. However, the molecular mechanisms underlying PCa progression are still unclear. Here we use a pair of prostate cell lines P69/M12, which have the same genetic background and the highly metastatic cell line M12 is a subline derived from P69, to identify the pathogenesis of PCa. We find that a key miRNA--miR186 is significantly reduced in M12 compared to that in P69. Further, we validate that miR186 is also downregulated in human PCa specimens, most significantly in the metastatic patient specimens. The low miR186 expression is correlated with poor patient survival. Through knockdown or overexpression of miR186 in PCa cell lines, we discover that miR186 strongly inhibits cell motility, invasive, soft-agar colony formation, 3D culture growth and vasculogenic mimicry (VM) formation capacity, as well as the epithelial-to-mesenchymal transition (EMT) process by downregulation of its target Twist1. Moreover, the inverse relationship between the expression levels of miR186 and Twist1 is confirmed in vivo tumor metastasis experiment and clinical specimens. Taken together, our findings demonstrate an important role of miR186/Twist1 axis in the regulation of PCa progression, suggesting a potential application of miR186/Twist1 in PCa treatment.

| S-EPMC5078081 | biostudies-other

Prostate Cancer Stem Cell Markers Drive Progression, Therapeutic Resistance, and Bone Metastasis.

Project description:Metastatic or recurrent tumors are the primary cause of cancer-related death. For prostate cancer, patients diagnosed with local disease have a 99% 5-year survival rate; however, this 5-year survival rate drops to 28% in patients with metastatic disease. This dramatic decline in survival has driven interest in discovering new markers able to identify tumors likely to recur and in developing new methods to prevent metastases from occurring. Biomarker discovery for aggressive tumor cells includes attempts to identify cancer stem cells (CSCs). CSCs are defined as tumor cells capable of self-renewal and regenerating the entire tumor heterogeneity. Thus, it is hypothesized that CSCs may drive primary tumor aggressiveness, metastatic colonization, and therapeutic relapse. The ability to identify these cells in the primary tumor or circulation would provide prognostic information capable of driving prostate cancer treatment decisions. Further, the ability to target these CSCs could prevent tumor metastasis and relapse after therapy allowing for prostate cancer to finally be cured. Here, we will review potential CSC markers and highlight evidence that describes how cells expressing each marker may drive prostate cancer progression, metastatic colonization and growth, tumor recurrence, and resistance to treatment.

| S-EPMC5485361 | biostudies-other

STAT3 regulated ARF expression suppresses prostate cancer metastasis.

Project description:Prostate cancer (PCa) is the most prevalent cancer in men. Hyperactive STAT3 is thought to be oncogenic in PCa. However, targeting of the IL-6/STAT3 axis in PCa patients has failed to provide therapeutic benefit. Here we show that genetic inactivation of Stat3 or IL-6 signalling in a Pten-deficient PCa mouse model accelerates cancer progression leading to metastasis. Mechanistically, we identify p19(ARF) as a direct Stat3 target. Loss of Stat3 signalling disrupts the ARF-Mdm2-p53 tumour suppressor axis bypassing senescence. Strikingly, we also identify STAT3 and CDKN2A mutations in primary human PCa. STAT3 and CDKN2A deletions co-occurred with high frequency in PCa metastases. In accordance, loss of STAT3 and p14(ARF) expression in patient tumours correlates with increased risk of disease recurrence and metastatic PCa. Thus, STAT3 and ARF may be prognostic markers to stratify high from low risk PCa patients. Our findings challenge the current discussion on therapeutic benefit or risk of IL-6/STAT3 inhibition.

| S-EPMC4525303 | biostudies-literature

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