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Prostate cancer cell-stromal cell crosstalk via FGFR1 mediates antitumor activity of dovitinib in bone metastases.

ABSTRACT: Bone is the most common site of prostate cancer (PCa) progression to a therapy-resistant, lethal phenotype. We found that blockade of fibroblast growth factor receptors (FGFRs) with the receptor tyrosine kinase inhibitor dovitinib has clinical activity in a subset of men with castration-resistant PCa and bone metastases. Our integrated analyses suggest that FGF signaling mediates a positive feedback loop between PCa cells and bone cells and that blockade of FGFR1 in osteoblasts partially mediates the antitumor activity of dovitinib by improving bone quality and by blocking PCa cell-bone cell interaction. These findings account for clinical observations such as reductions in lesion size and intensity on bone scans, lymph node size, and tumor-specific symptoms without proportional declines in serum prostate-specific antigen concentration. Our findings suggest that targeting FGFR has therapeutic activity in advanced PCa and provide direction for the development of therapies with FGFR inhibitors.

SUBMITTER: Wan X

PROVIDER: S-EPMC4407499 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature

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Prostate cancer cell-stromal cell crosstalk via FGFR1 mediates antitumor activity of dovitinib in bone metastases.

Wan Xinhai X Corn Paul G PG Yang Jun J Palanisamy Nallasivam N Starbuck Michael W MW Efstathiou Eleni E Li Ning Tapia Elsa M EM Zurita Amado J AJ Aparicio Ana A Ravoori Murali K MK Vazquez Elba S ES Robinson Dan R DR Wu Yi-Mi YM Cao Xuhong X Iyer Matthew K MK McKeehan Wallace W Kundra Vikas V Wang Fen F Troncoso Patricia P Chinnaiyan Arul M AM Logothetis Christopher J CJ Navone Nora M NM

Science translational medicine 20140901 252

Bone is the most common site of prostate cancer (PCa) progression to a therapy-resistant, lethal phenotype. We found that blockade of fibroblast growth factor receptors (FGFRs) with the receptor tyrosine kinase inhibitor dovitinib has clinical activity in a subset of men with castration-resistant PCa and bone metastases. Our integrated analyses suggest that FGF signaling mediates a positive feedback loop between PCa cells and bone cells and that blockade of FGFR1 in osteoblasts partially mediate ...[more]

PMID: 25186177

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Project description:IntroductionLeptin is a metabolic peptide hormone produced by adipocytes, with proven roles in proliferation of prostate cancer cells and of prostate cells in animal models of benign prostatic hyperplasia (BPH). Thus, the role of leptin as a molecular link connecting BPH and lower urinary tract symptoms (LUTS) suggestive of BPH with metabolic symptoms appears feasible but is still unknown. In fact, a connection between metabolic syndrome and BPH is becoming increasingly evident from epidemiologic studies. Key factors of Lower urinary tract symptoms associated with benign prostatic hyperplasia (BPH/LUTS) are increased prostate smooth muscle tone, and prostate enlargement. Here, we examined the effects of leptin on contraction of human prostate smooth muscle and on growth of stromal cells.MethodsWe performed microarray analysis to identify genes (fold change ≥ 1.5) associated with BPH/LUTS progression, such as those involved in proliferation, apoptosis, and mitochondrial metabolism, in rat prostate tissue (data from GSE129561). We then used electric field stimulation (EFS) to induce frequency-dependent, neurogenic contractions of human prostate strips, which were enhanced by leptin. We also examined the effect of leptin on human prostate stromal cells (WPMY-1) and found increased cell proliferation and viability upon exposure. To explore the underlying mechanism, we conducted mitochondrial stress assay using near-infrared (NIR) fluorescent dye and flow cytometry (FACS) analysis and observed reduced cellular apoptosis and preserved mitochondrial membrane potential (∆ψM) after leptin treatment.ResultsMicroarray analysis reveals that leptin regulates prostate smooth muscle contraction and stromal cell proliferation, shedding new light on its involvement in BPH/LUTS pathogenesis and mitochondrial function. We found that leptin enhanced the proliferation rate of prostate stromal cells relative to the control group (0.67 ± 0.05 vs 0.54 ± 0.08, p-value= 0.024). Moreover, leptin (100 ng/mL) potentiated the frequency-dependent, neurogenic contractions of prostate strips elicited by EFS (p= 0.047 between leptin and control group). We also show that leptin treatment increased the mitochondrial membrane potential of prostate stromal cells and inhibited mitochondrial apoptosis.DiscussionOur results indicate that leptin stimulates the contractility and proliferation of smooth muscle and stromal cells in the human prostate, implying a potential role for leptin in exacerbating BPH/LUTS in obese men. Leptin modulation may be a beneficial therapeutic strategy for patients with metabolic syndrome and BPH/LUTS. Further studies are warranted to elucidate the mechanisms and implications of the leptin system in BPH/LUTS.

Project description:Background:With the occurrence and improvement of immunohistochemistry and other pathological diagnostic techniques, gastrointestinal stromal tumor (GIST) has been gradually recognized. With the prolonged survival of patients with GISTs, reports about the bone metastasis of GIST increased. However, the knowledge of GISTs is rather limited due to its very low incidence. Methods:Cochrane and Medline database (via PubMed) were searched in July 2019 with related keywords to acquire the literature related to the bone metastasis of GIST. Then, the literature was reviewed and references were also scanned to identify the possible related reports. Study data comprising age, sex, primary location, metastasis interval time, immunohistochemistry index, management and prognosis were recorded and analyzed. Results:Forty-five patients with bone metastases of GIST, with a mean age of 61.09 years, were included. The small intestine and stomach were the most common primary sites, followed by the rectum. Patients with small intestine primary sites had bone metastases that occurred earlier than the bone metastases stomach and rectum primary sites. The spine was the most common site of bony metastases. The mean survival time after GIST diagnosis was more than 64.02 months. Patients younger than 60 years old had a worse prognosis than those older than 60 years old. Furthermore, patients with spinal involvement had a worse prognosis than those without spinal involvement. Surgical interventions combined with targeted therapies guaranteed a better prognosis. Conclusion:Bone metastasis of GIST, which mainly occurs in the spine, is rather rare. Patients with GISTs of the small intestine and stomach suffered from bone metastasis more frequently and earlier than patients with GISTs in other primary sites. Age, sex, primary tumor location, treatment mode for the primary lesions and metastases, and spine involvement may be potential factors that affect the prognosis of GIST patients with bone metastases.

Dataset Information

Prostate cancer cell-stromal cell crosstalk via FGFR1 mediates antitumor activity of dovitinib in bone metastases.

Publications

Prostate cancer cell-stromal cell crosstalk via FGFR1 mediates antitumor activity of dovitinib in bone metastases.

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