Stromal impact on tumor growth and lymphangiogenesis in human carcinoma xenografts

Squamous cell carcinomas (SCCs) arising in the oral cavity are associated with poor survival, mainly due to metastatic disease. In contrast, skin SCCs rarely metastasize and are usually curable. To study influence of tongue and skin stroma on cancer growth and induction of lymphangiogenesis, xenograft tumors of human carcinoma cells were established either in tongue or skin of BALB/c nude mice. Two oral and two skin SCC cell lines were used, as well as an endometrial adenocarcinoma cell line. Tongue tumors established from all cell lines were larger than corresponding skin tumors. Peritumoral lymphatic vessel density was up to five times higher in tongue than in corresponding skin tumors, and mRNA level of the lymphangiogenic growth factor vascular endothelial growth factor (VEGF)-C was twice as high in tongue tumors compared with corresponding skin tumors. Contrary to lymphatic vessel density, blood vessel density was higher in skin tumors than in tongue tumors. In a cohort of patient samples, lymphatic vessel density was found to be higher in tongue SCCs compared with skin SCCs, supporting a clinical relevance of our findings. Our results show that the tumor stroma has a profound impact on cancer growth and induction of lymphangiogenesis and angiogenesis. The difference in lymphatic vessel density between tongue and skin tumors may be important in directing metastatic potential of tumors arising in these organs

Intervention fidelity and process outcomes of the IMMENSE study, a pharmacist-led interdisciplinary intervention to improve medication safety in older hospitalized patients

What is known and Objective - The majority of hospitalized older patients experience medication-related problems (MRPs), and there is a call for interventions to solve MRPs and improve clinical outcomes like medical visits. The IMMENSE study is a randomized controlled trial investigating the impact of a pharmacist-led interdisciplinary intervention on emergency medical visits. Its multistep intervention is based on the integrated medicines management methodology and includes a follow-up step with primary care. This study aims to describe how the intervention in the IMMENSE study was delivered and its process outcomes. Methods - The study includes the 221 intervention patients in the per-protocol group of the IMMENSE study. Both intervention delivery, reasons for not performing interventions and process outcomes were registered daily by the study pharmacists in a Microsoft Access® database. Process outcomes were medication discrepancies, MRPs and how the team solved these. Results and discussion - A total of 121 (54.8%) patients received all intervention steps if appropriate. All patients received medication reconciliation (MedRec) and medication Review (MedRev) (step 1 and 2), while between 10% and 20% of patients were missed for medication list in discharge summary (step 3), patient counselling (step 4), or communication with general practitioner and nurse (step 5). A total of 437 discrepancies were identified in 159 (71.9%) patients during MedRec, and 1042 MRPs were identified in 209 (94.6%) patients during MedRev. Of these, 292 (66.8%) and 700 (67.2%), respectively, were communicated to and solved by the interdisciplinary team during the hospital stay. What is new and Conclusion - The fidelity of the single steps of the intervention was high even though only about half of the patients received all intervention steps. The impact of the intervention may be influenced by not implementing all steps in all patients, but the many discrepancies and MRPs identified and solved for the patients could explain a potential effect of the IMMENSE study

Phosphorylation of steroid receptor coactivator-3 (SRC-3) at serine 857 is regulated by the p38 MAPK-MK2 axis and affects NF-κB-mediated transcription

Steroid receptor coactivator-3 (SRC-3) regulates the activity of both nuclear hormone receptors and a number of key transcription factors. It is implicated in the regulation of cell proliferation, inflammation and in the progression of several common cancers including breast, colorectal and lung tumors. Phosphorylation is an important regulatory event controlling the activities of SRC-3. Serine 857 is the most studied phospho-acceptor site, and its modification has been reported to be important for SRC-3-dependent tumor progression. In this study, we show that the stress-responsive p38MAPK-MK2 signaling pathway controls the phosphorylation of SRC-3 at S857 in a wide range of human cancer cells. Activation of the p38MAPK-MK2 pathway results in the nuclear translocation of SRC-3, where it contributes to the transactivation of NF-kB and thus regulation of IL-6 transcription. The identification of the p38MAPK-MK2 signaling axis as a key regulator of SRC-3 phosphorylation and activity opens up new possibilities for the development and testing of novel therapeutic strategies to control both proliferative and metastatic tumor growth

A novel role for atypical MAPK kinase ERK3 in regulating breast cancer cell morphology and migration

ERK3 is an atypical Mitogen-activated protein kinase (MAPK6). Despite the fact that the Erk3 gene was originally identified in 1991, its function is still unknown. MK5 (MAP kinase- activated protein kinase 5) also called PRAK is the only known substrate for ERK3. Recently, it was found that group I p21 protein activated kinases (PAKs) are critical effectors of ERK3. PAKs link Rho family of GTPases to actin cytoskeletal dynamics and are known to be involved in the regulation of cell adhesion and migration. In this study we demonstrate that ERK3 protein levels are elevated as MDA-MB-231 breast cancer cells adhere to collagen I which is concomitant with changes in cellular morphology where cells become less well spread following nascent adhesion formation. During this early cellular adhesion event we observe that the cells retain protrusive activity while reducing overall cellular area. Interestingly exogenous expression of ERK3 delivers a comparable reduction in cell spread area, while depletion of ERK3 expression increases cell spread area. Importantly, we have detected a novel specific endogenous ERK3 localization at the cell periphery. Furthermore we find that ERK3 overexpressing cells exhibit a rounded morphology and increased cell migration speed. Surprisingly, exogenous expression of a kinase inactive mutant of ERK3 phenocopies ERK3 overexpression, suggesting a novel kinase independent function for ERK3. Taken together our data suggest that as cells initiate adhesion to matrix increasing levels of ERK3 at the cell periphery are required to orchestrate cell morphology changes which can then drive migratory behavior