The prostate metastasis suppressor gene NDRG1 differentially regulates cell motility and invasion.

Experimental and clinical evidence suggests that N-myc downregulated gene 1 (NDRG1) functions as a suppressor of prostate cancer metastasis. Elucidating pathways that drive survival and invasiveness of NDRG1-deficient prostate cancer cells can help in designing therapeutics to target metastatic prostate cancer cells. However, the molecular mechanisms that lead NDRG1-deficient prostate cancer cells to increased invasiveness remain largely unknown. In this study, we demonstrate that NDRG1-deficient prostate tumors have decreased integrin expression and reduced cell adhesion and motility. Our data indicate that loss of NDRG1 differentially affects Rho GTPases. Specifically, there is a downregulation of active RhoA and Rac1 GTPases with a concomitant upregulation of active Cdc42 in NDRG1-deficient cells. Live cell imaging using a fluorescent sensor that binds to polymerized actin revealed that NDRG1-deficient cells have restricted actin dynamics, thereby affecting cell migration. These cellular and molecular characteristics are in sharp contrast to what is expected after loss of a metastasis suppressor. We further demonstrate that NDRG1-deficient cells have increased resistance to anoikis and increased invasiveness which is independent of its elevated Cdc42 activity. Furthermore, NDRG1 regulates expression and glycosylation of EMMPRIN, a master regulator of matrix metalloproteases. NDRG1 deficiency leads to an increase in EMMPRIN expression with a concomitant increase in matrix metalloproteases and thus invadopodial activity. Using a three-dimensional invasion assay and an in vivo metastasis assay for human prostate xenografts, we demonstrate that NDRG1-deficient prostate cancer cells exhibit a collective invasion phenotype and are highly invasive. Thus, our findings provide novel insights suggesting that loss of NDRG1 leads to a decrease in actin-mediated cellular motility but an increase in cellular invasion, resulting in increased tumor dissemination which positively impacts metastatic outcome.

Long-term Outcome of Prostate Cancer Patients Who Exhibit Biochemical Failure Despite Salvage Radiation Therapy After Radical Prostatectomy.

OBJECTIVES: Salvage radiation therapy (SRT) is an effective treatment for recurrent prostate cancer (PCa) after radical prostatectomy. We report the long-term outcome of men who developed biochemical recurrence (BCR) after SRT and were treated >14 years ago. METHODS: In total, 61 patients treated with SRT from 1992 to 2000 at our institution were identified. Survival was calculated by Kaplan-Meier method. Log-rank test and Cox regression were used to determine significance of clinical parameters. RESULTS: The median follow-up was 126 months (interquartile range, 66-167 mo). Thirty-four (56%) had prostate-specific antigen (PSA) failure after SRT. At 10 years, overall survival (OS) was 67%, freedom from PSA failure (FFPF) was 33%, prostate cancer-specific survival (PCSS) was 84%, and distant metastases-free survival (DMFS) was 84%. Pathologic T-stage, Gleason score, seminal vesicle involvement, and pre-SRT PSA were associated with FFPF. For patients who failed SRT, the median time to BCR after SRT was 30 mo. A total of 19 (68%) received androgen deprivation therapy. The median OS was 13.6 years. At 10 years from time of BCR, OS was 59%, PCSS was 73%, DMFS was 75%, and castration-resistant-free survival was 70%. Early SRT failure correlated with significantly decreased DMFS and PCSS. Ten-year DMFS from SRT was 43% (BCR≤1 y) versus 91% (BCR>1 y). CONCLUSIONS: Extended follow-up demonstrates that despite SRT failure, PCSS remains high in select patients. Early failure (≤1 y after SRT) predicted for significantly worse outcome and may represent a subgroup with more aggressive disease that may be considered for further prospective clinical studies.

Review of evolving etiologies, implications and treatment strategies for the superior vena cava syndrome.

Superior vena cava syndrome (SVCS) is a relatively common sequela of mediastinal malignancies and may cause significant patient distress. SVCS is a medical emergency if associated with laryngeal or cerebral edema. The etiologies and management of SVCS have evolved over time. Non-malignant SVCS is typically caused by infectious etiologies or by thrombus in the superior vena cava and can be managed with antibiotics or anti-coagulation therapy, respectively. Radiation therapy (RT) has long been a mainstay of treatment of malignant SVCS. Chemotherapy has also been used to manage SVCS. In the past 20 years, percutaneous stenting of the superior vena cava has emerged as a viable option for SVCS symptom palliation. RT and chemotherapy are still the only modalities that can provide curative treatment for underlying malignant etiologies of SVCS. The first experiences with treating SVCS with RT were reported in the 1970's, and several advances in RT delivery have subsequently occurred. Hypo-fractionated RT has the potential to be a more convenient therapy for patients and may provide equal or superior control of underlying malignancies. RT may be combined with stenting and/or chemotherapy to provide both immediate symptom palliation and long-term disease control. Clinicians should tailor therapy on a case-by-case basis. Multi-disciplinary care will maximize treatment expediency and efficacy.

Solitary recurrence of castration-resistant prostate cancer with low or undetectable levels of prostate specific antigen salvaged with local ablative radiation therapy: A case report.

Prostate cancer recurrences are usually first detected by increased levels of prostate specific antigen (PSA), and systemic therapy is often initiated if distant metastasis is confirmed. However, low or nearly undetectable levels of PSA in the modern era of ultrasensitive PSA assay may be difficult to interpret in patients with a history of prostate cancer. Deciding whether to initiate additional systemic therapy in limited indolent metastatic disease while balancing the quality of life of the patient and ensuring the oncologic control of the disease may be challenging. In the present study, the case of a biopsy-confirmed solitary spine recurrence of prostate cancer with nearly undetectable but persistent levels of PSA (0.05 ng/ml) is reported. Treatment of the recurrence with local ablative radiotherapy improved the pain experienced by the patient, and reduced his levels of PSA to undetectable limits (<0.05 ng/ml). Repeated imaging analysis, PSA assay and clinical assessment demonstrated durable control of the disease without the requirement for additional systemic treatments. The present case highlighted the importance of initiating appropriate work-up according to the clinical scenario. Local treatment for solitary or oligometastatic recurrence of prostate cancer may enhance the effectiveness of current therapeutic strategies and benefit certain patients.