Urinary C-Met, A Novel Biomarker Of Metastatic Prostate Cancer

Purpose/Objective(s)Prostate cancer remains the second most common cause of cancer deaths of men in the United States, nearly all of which are from metastatic disease. c-Met, a receptor tyrosine kinase, is overexpressed in a number of malignancies including metastatic prostate cancer. c-Met ectodomain shedding in the urine of mice has been shown to correlate with tumor burden. We hypothesized that urinary c-Met in humans may correlate with metastatic prostate cancer and that c-Met may play a central role in the development of metastatic disease.Materials/MethodsIngenuity Pathways Analysis, Unified Human Interactome, and Myriad ProNet Interface were used to identify both experimentally and literature derived protein interactions of c-Met. PubMed was then used to identify which c-Met-interacting proteins directly related to metastatic prostate cancer. To measure the concordance of c-Met levels with metastatic prostate cancer we measured urinary c-Met levels in patients undergoing radiation therapy. Included in our study were 72 patients with localized prostate cancer, 31 patients with metastatic cancer, and 20 patients without prostate cancer. Urine was stored at −20°C until time of use, then centrifuged at 3000 rpm for 10 min at 4°C, and supernatant was used for assay. To quantitate urinary c-Met, specimens were analyzed using an electrochemiluminescent immunoassay in quadruplicate.ResultsDirected protein-protein interactomes and network analysis combined with a detailed literature search revealed 39 proteins directly related to c-Met and metastatic prostate cancer. Nine proteins have been shown to be downregulated and 30 proteins upregulated in metastatic prostate cancer. Of these, 21 proteins were experimentally or computationally derived interactions. Electrochemiluminescent immunoassay showed urine of metastatic patients had significantly higher levels of c-Met compared to patients with localized prostate cancer or no prostate cancer (mean 245 pg/mg vs. 177 pg/mg, p = 0.006, Students' t test). Gleason score, T stage, and PSA did not significantly correlate with c-Met levels. Specificity and sensitivity of urinary c-Met in metastatic prostate cancer with values ≥250 pg/mg is 84.4% and 35.5%, respectively.ConclusionsUrinary c-Met was shown to be significantly elevated in patients with metastatic prostate cancer supporting prior literature showing elevations in serum and tissue. c-Met may serve as a central initiator of the metastatic process as demonstrated by network analysis. Additional studies are ongoing in an attempt to determine if c-Met can be used to predict the development of metastatic disease prior to clinical metastases in patients with prostate cancer. Purpose/Objective(s)Prostate cancer remains the second most common cause of cancer deaths of men in the United States, nearly all of which are from metastatic disease. c-Met, a receptor tyrosine kinase, is overexpressed in a number of malignancies including metastatic prostate cancer. c-Met ectodomain shedding in the urine of mice has been shown to correlate with tumor burden. We hypothesized that urinary c-Met in humans may correlate with metastatic prostate cancer and that c-Met may play a central role in the development of metastatic disease. Prostate cancer remains the second most common cause of cancer deaths of men in the United States, nearly all of which are from metastatic disease. c-Met, a receptor tyrosine kinase, is overexpressed in a number of malignancies including metastatic prostate cancer. c-Met ectodomain shedding in the urine of mice has been shown to correlate with tumor burden. We hypothesized that urinary c-Met in humans may correlate with metastatic prostate cancer and that c-Met may play a central role in the development of metastatic disease. Materials/MethodsIngenuity Pathways Analysis, Unified Human Interactome, and Myriad ProNet Interface were used to identify both experimentally and literature derived protein interactions of c-Met. PubMed was then used to identify which c-Met-interacting proteins directly related to metastatic prostate cancer. To measure the concordance of c-Met levels with metastatic prostate cancer we measured urinary c-Met levels in patients undergoing radiation therapy. Included in our study were 72 patients with localized prostate cancer, 31 patients with metastatic cancer, and 20 patients without prostate cancer. Urine was stored at −20°C until time of use, then centrifuged at 3000 rpm for 10 min at 4°C, and supernatant was used for assay. To quantitate urinary c-Met, specimens were analyzed using an electrochemiluminescent immunoassay in quadruplicate. Ingenuity Pathways Analysis, Unified Human Interactome, and Myriad ProNet Interface were used to identify both experimentally and literature derived protein interactions of c-Met. PubMed was then used to identify which c-Met-interacting proteins directly related to metastatic prostate cancer. To measure the concordance of c-Met levels with metastatic prostate cancer we measured urinary c-Met levels in patients undergoing radiation therapy. Included in our study were 72 patients with localized prostate cancer, 31 patients with metastatic cancer, and 20 patients without prostate cancer. Urine was stored at −20°C until time of use, then centrifuged at 3000 rpm for 10 min at 4°C, and supernatant was used for assay. To quantitate urinary c-Met, specimens were analyzed using an electrochemiluminescent immunoassay in quadruplicate. ResultsDirected protein-protein interactomes and network analysis combined with a detailed literature search revealed 39 proteins directly related to c-Met and metastatic prostate cancer. Nine proteins have been shown to be downregulated and 30 proteins upregulated in metastatic prostate cancer. Of these, 21 proteins were experimentally or computationally derived interactions. Electrochemiluminescent immunoassay showed urine of metastatic patients had significantly higher levels of c-Met compared to patients with localized prostate cancer or no prostate cancer (mean 245 pg/mg vs. 177 pg/mg, p = 0.006, Students' t test). Gleason score, T stage, and PSA did not significantly correlate with c-Met levels. Specificity and sensitivity of urinary c-Met in metastatic prostate cancer with values ≥250 pg/mg is 84.4% and 35.5%, respectively. Directed protein-protein interactomes and network analysis combined with a detailed literature search revealed 39 proteins directly related to c-Met and metastatic prostate cancer. Nine proteins have been shown to be downregulated and 30 proteins upregulated in metastatic prostate cancer. Of these, 21 proteins were experimentally or computationally derived interactions. Electrochemiluminescent immunoassay showed urine of metastatic patients had significantly higher levels of c-Met compared to patients with localized prostate cancer or no prostate cancer (mean 245 pg/mg vs. 177 pg/mg, p = 0.006, Students' t test). Gleason score, T stage, and PSA did not significantly correlate with c-Met levels. Specificity and sensitivity of urinary c-Met in metastatic prostate cancer with values ≥250 pg/mg is 84.4% and 35.5%, respectively. ConclusionsUrinary c-Met was shown to be significantly elevated in patients with metastatic prostate cancer supporting prior literature showing elevations in serum and tissue. c-Met may serve as a central initiator of the metastatic process as demonstrated by network analysis. Additional studies are ongoing in an attempt to determine if c-Met can be used to predict the development of metastatic disease prior to clinical metastases in patients with prostate cancer. Urinary c-Met was shown to be significantly elevated in patients with metastatic prostate cancer supporting prior literature showing elevations in serum and tissue. c-Met may serve as a central initiator of the metastatic process as demonstrated by network analysis. Additional studies are ongoing in an attempt to determine if c-Met can be used to predict the development of metastatic disease prior to clinical metastases in patients with prostate cancer.