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NELL‐1 (Nel‐like molecule‐1) is a secreted osteogenic growth factor first identified in human craniosynostosis (CS) patients. NELL‐1 protein has been observed to promote bone and cartilage differentiation and to suppress adipogenesis in both in vitro and in vivo models. Despite these findings, the cell surface receptors of NELL‐1 have remained unknown. In this study, we observed for the first time that NELL‐1 promotes cell adherence in multiple cell lines, including ST2, C3H10T1/2, M2‐10B4, ATDC5, and MC3T3 cells. Additionally, we found that NELL‐1 binds to extracellular Integrinβ1 and induces cell focal adhesion. By utilizing siRNA methods, we determined that NELL‐1 cell surface binding and enhanced cell attachment were dependent on Integrinβ1 expression. Finally, we observed that pre‐coating of culture dishes or PLGA (polylactic‐co‐glycolic acid) scaffold with NELL‐1 resulted in a significant increase in both cell attachment and osteogenic differentiation. Our results identify for the first time a cell surface target of NELL‐1, Integrinβ1, and elucidate new functions of NELL‐1 in promoting cell adherence and osteogenic differentiation. J. Cell. Biochem. 113: 3620–3628, 2012. © 2012 Wiley Periodicals, Inc.

BackgroundThe biological and clinical significance of multifocal and multicentric (MF/MC) breast cancers and the choice of appropriate surgical treatment for these tumors are still debated.Methods1158 women operated on for a stage I-III breast cancer were included in this retrospective study; clinical and pathological data were obtained from the institutional database of the Department of Oncology of the University of Siena, Italy. The impact of MF/MC breast cancers on patterns of recurrence and breast cancer specific survival (BCSS) was investigated in relation to the type of surgical treatment.ResultsMF and MC cancers were present in 131 cases (11.3%) and 60 cases (5.2%) respectively and were more frequently treated with mastectomy (55 MF and 60 MC cancers, 81.2%) than with breast conserving surgery (36 MF cancers, 18.9%; p < 0.001). MF and MC breast cancers were associated with a worse prognosis with a BCSS of 154 months compared to 204 months of unicentric cancers (p < 0.001). In multivariate analysis, MF/MC cancers were independent prognostic factors for BCSS together with higher number of metastatic axillary nodes, absence of estrogen receptors and high proliferative activity. MF and MC cancers were related to a significantly shorter BCSS in patients submitted to mastectomy as well as those submitted to breast conserving surgery. Relapse at any site was higher in the subgroup of MF and MC cancers but the incidence of loco-regional and distant recurrences did not differ between patients treated with mastectomy or breast conserving surgery.ConclusionsOur results indicate that MF/MC cancers have a negative impact on prognosis and are related to higher loregional and distant relapse independently from the type of surgery performed. Adjuvant therapies did not modify the poorer outcome, but in patients receiving adjuvant anthacyclines, the differences with unicentric tumors were reduced. Our data support the hypothesis that MF/MC tumors may have a worse biological behavior and that the presence of multiple foci should be considered in planning adjuvant treatments.

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IHCP combined with cytoreductive surgery involves a high risk of morbidity, but postoperative complications could be resolved favorably in most cases with correct patient selection and adequate postoperative care. Tumor residual and advanced age significantly increase the risk of morbidity after this procedure.