A novel role for Plk4 in regulating cell spreading and motility.

Polo family kinase 4 (Plk4) is required for mitotic progression, and is haploinsufficient for tumor suppression and timely hepatocyte polarization in regenerating liver. At the same time, recent evidence suggests that Plk4 expression may have a role in clinical cancer progression, although the mechanisms are not clear. Here we identify a gene expression pattern predictive of reduced motility in Plk4(+/-) murine embryonic fibroblasts (MEFs) and validate this prediction with functional assays of cell spreading, migration and invasion. Increased Plk4 expression enhances cell spreading in Plk4(+/-) MEFs and migration in human embryonic kidney 293T cells, and increases invasion by DLD-1 colon cancer cells. Plk4 depletion impairs invasion of wild-type MEFs and suppresses invasion by MDA-MB231 breast cancer cells. Cytoskeletal reorganization and development of polarity are impaired in Plk4-deficient cells that have been stimulated to migrate. Endogenous Plk4 phosphorylated at the autophosphorylation site S305 localizes to the protrusions of motile cells, coincident with the RhoA GEF Ect2, GTP-bound RhoA and the RhoA effector mDia. Taken together, our findings reveal an unexpected activity of Plk4 that promotes cell migration and may underlie an association between increased Plk4 expression, cancer progression and death from metastasis in solid tumor patients.

Long-term outcomes following resection of retroperitoneal recurrence of colorectal cancer.

BACKGROUND: The role of curative-intent surgery for retroperitoneal recurrence (RPR) of colorectal cancer (CRC) remains controversial. We previously showed 0% mortality and acceptable morbidity in patients who underwent resection of RPR.(1) Here we examine long-term overall and disease-free survival (OS, DFS). METHODS: We identified patients who underwent resection for RPR of CRC between 01/1999 and 02/2010 from two prospective CRC databases. RESULTS: The study cohort was composed of 48 patients (26 women) whose median age was 60 (36-80) years. Eleven patients had previously undergone resection of a different focus of disease recurrence, and 8 patients had additional site(s) of distant metastatic disease at the time of RPR resection. Following surgery for RPR, 5 patients were left with gross residual disease, and 6 had microscopically positive margins. Median follow-up was 32 (3-127) months. At last follow-up, 13 patients had died of cancer and 1 of other causes. For the entire cohort of 48 patients, 5-year OS was 70% (median 80 mo). In univariate analysis, OS was reduced in younger patients (p = 0.003) and in those with gross residual disease (p = 0.033). In patients who had grossly complete resection, 5-year DFS was 49% (median 38 mo). Predictors of reduced DFS on multivariable analysis were young age and R1 resection. CONCLUSION: OS and DFS after resection of RPR in well-selected patients were favorable. Patients with RPR of CRC should be considered for curative-intent surgery with careful discussion at multidisciplinary cancer conference.