Upregulated Heat Shock Proteins After Hyperthermic Chemotherapy Point to Induced Cell Survival Mechanisms in Affected Tumor Cells From Peritoneal Carcinomatosis.

In patients with peritoneal carcinomatosis cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (HIPEC) represents a promising treatment strategy. Here, we studied the role of hyperthermic chemotherapy on heat shock protein (HSP) expression and induction of tumor cell death and survival. HSP27, HSP70, and HSP90 combined with effects on tumor cell proliferation and chemosensitivity were analyzed in human colon cancer. Hyperthermic chemotherapy resulted in significant HSP27/HSP70 and HSP90 gene/protein overexpression in analyzed HT-29/SW480/SW620 colon cancer cells and peritoneal metastases from patients displaying amplified expression of proliferation markers, proliferating cell nuclear antigen and antiapoptotic protein Bcl-xL. Moreover, functionally increased chemoresistance against 5-fluorouracil/mitomycin C and oxaliplatin after hyperthermic chemotherapy points to induced survival mechanisms in cancer cells. In conclusion, the results indicate that intracellular HSP-associated antiapoptotic and proliferative effects after hyperthermic chemotherapy negatively influence beneficial effects of hyperthermic chemotherapy-induced cell death. Therefore, blocking HSPs could be a promising strategy to further improve the rate of tumor cell death and outcome of patients undergoing HIPEC therapy.

Exclusive inhibition of PI3K/Akt/mTOR signaling is not sufficient to prevent PDGF-mediated effects on glycolysis and proliferation in colorectal cancer.

Platelet-derived growth factor (PDGF) and signaling via its receptors plays a crucial role in tumor cell proliferation and thus may represent an attractive target besides VEGF/EGFR-based antibody therapies. In this study we analyzed the influence of PDGF in colorectal cancer. PDGF was expressed intensively in early and even more intensively in late stage primary CRCs. Like VEGF, PDGF enhanced human colon cancer proliferation, and increased oxidative glycolytic activity, and activated HIF1α and c-Myc in vitro. PDGF activated the PI3K/Akt/mTOR pathway while leaving MAPK signaling untouched. Further dissection showed that inhibition of Akt strongly impeded cancer cell growth while inhibition of PI3K did not. MAPK analysis suggested an inhibitory crosstalk between both pathways, thus explaining the different effects of the Akt and PI3K inhibitors on cancer cell proliferation. PDGF stimulates colon cancer cell proliferation, and prevents inhibitor induced apoptosis, resulting in tumor growth. Therefore inhibition of PDGF signaling seems to be a promising target in colorectal cancer therapy. However, due to the multifaceted nature of the intracellular PDGF signaling, careful intervention strategies are needed when looking into specific signaling pathways like PI3K/Akt/mTOR and MAPK.

TLR7 and TLR8 expression increases tumor cell proliferation and promotes chemoresistance in human pancreatic cancer.

Chronic inflammation as an important epigenetic and environmental factor for putative tumorigenesis and tumor progression may be associated with specific activation of Toll-like receptors (TLR). Recently, carcinogenesis has been suggested to be dependent on TLR7 signaling. In the present study, we determined the role of both TLR7 and TLR8 expression and signaling in tumor cell proliferation and chemoresistance in pancreatic cancer. Expression of TLR7/TLR8 in UICC stage I-IV pancreatic cancer, chronic pancreatitis, normal pancreatic tissue and human pancreatic (PANC1) cancer cell line was examined. For in vitro/in vivo studies TLR7/TLR8 overexpressing PANC1 cell lines were generated and analyzed for effects of (un-)stimulated TLR expression on tumor cell proliferation and chemoresistance. TLR expression was increased in pancreatic cancer, with stage-dependent upregulation in advanced tumors, compared to earlier stages and chronic pancreatitis. Stimulation of TLR7/TLR8 overexpressing PANC1 cells resulted in elevated NF-κB and COX-2 expression, increased cancer cell proliferation and reduced chemosensitivity. More importantly, TLR7/TLR8 expression increased tumor growth in vivo. Our data demonstrate a stage-dependent upregulation of both TLR7 and TLR8 expression in pancreatic cancer. Functional analysis in human pancreatic cancer cells point to a significant role of both TLRs in chronic inflammation-mediated TLR7/TLR8 signaling leading to tumor cell proliferation and chemoresistance.

A comparison of the MARA and the AdvanSync functional appliances in the treatment of Class II malocclusion.

OBJECTIVES: To determine the skeletal and dentoalveolar effects produced by the MARA and the AdvanSync functional appliances in the treatment of growing patients with Class II malocclusion. MATERIALS AND METHODS: A retrospective study was conducted using lateral cephalograms of patients consecutively treated with MARA (n  =  40) and AdvanSync (n  =  30) during their skeletal growth spurt as evaluated by the improved cervical vertebral maturation method. A comparison was made with 24 untreated Class II control subjects obtained from the University of Michigan growth study and matched with the experimental groups for skeletal age, sex, and craniofacial morphology. Cephalograms were taken at three time points: (T1) pretreatment, (T2) postfunctional appliance treatment, and (T3) fixed orthodontic treatment completion. Treatment changes were evaluated between the time points using 35 variables. Data were analyzed using one-way analysis of variance and Scheffe's post hoc test. RESULTS: At the postfunctional appliances' phase (T2-T1), both appliances showed significant increases in total mandibular length, ramus height, and anterior/posterior facial height. The AdvanSync resulted in significant restriction of maxillary growth, 1° more than MARA. This effect continued during the fixed orthodontic treatment stage (T3-T2). The net changes (T3-T1) revealed significant mandibular growth enhancement with MARA (+2.7mm) and significant headgear effect with AdvanSync. Both appliances caused 5° flaring in mandibular incisors as well as significant decreases in overjet and overbite. The treatment time for AdvanSync was 1 year less than MARA. CONCLUSION: The MARA and the AdvanSync resulted in normalization of the Class II malocclusion. The AdvanSync showed more headgear effect but less mandibular length enhancement than MARA did. Both appliances showed similar dentoalveolar changes.