11 results found
Froeling FEM, Stebbing J, 2014, Uncaria tomentosa, the cat's whiskers or claws?, LANCET ONCOLOGY, Vol: 15, Pages: 1299-1300, ISSN: 1470-2045
Froeling FEM, Seckl MJ, 2014, Gestational trophoblastic tumours: an update for 2014., Curr Oncol Rep, Vol: 16
Gestational trophoblastic disease describes a variety of pregnancy-related diseases including the premalignant conditions of a partial and complete hydatidiform mole and the malignant disorders of invasive mole, choriocarcinoma and the rare placental-site trophoblastic tumour and epithelioid trophoblastic tumour. The availability of a highly sensitive tumour marker in the form of human chorionic gonadotrophin, the chemosensitive character of the disease with effective treatment strategies and centralization of care of a rare group of diseases has resulted in excellent survival rates, which can exceed 98 %. This review gives a general overview of gestational trophoblastic disease, the most recent insights in aetiology and pathology and a summary of the different management strategies.
Arumugam P, Partelli S, Coleman SJ, et al., 2013, Ezrin expression is an independent prognostic factor in gastro-intestinal cancers., J Gastrointest Surg, Vol: 17, Pages: 2082-2091
BACKGROUND: Ezrin, a member of the ezrin-radixin-moesin (ERM) family of plasma membrane-cytoskeleton linker proteins, has been associated with metastatic behavior. METHODOLOGY: Microarrayed pathological tissues of surgically resected colorectal cancer liver metastasis (CRLM) and whole tissue sections of cancer of the ampulla of Vater (CAV) were analyzed to determine ezrin expression levels and correlation with survival. The requirement of ezrin in invasive capability was assessed using in vitro assays. RESULTS: Surgically resected CAV showing a low ezrin score have a better 5-year disease-specific survival than those showing a high ezrin score (P < 0.0001). Similarly, high ezrin expression at the invasive front of CRLM resulted in poor disease-free survival (P = 0.05). Multivariate analysis demonstrated high ezrin expression to be an independent adverse prognostic factor for CAV (hazard ratio (HR) 15.22 (95 % confidence interval (CI) 1.98-117.03), P < 0.01) and CRLM (HR 6.42 (95 % CI 1.01-52.43), P = 0.05), among other clinically relevant variables such as lymph node metastasis (for CAV) and the presence of extrahepatic disease, large hepatic metastases (>5 cm), and close surgical resection margins (<5 mm) (all for CRLM). In vitro experiments indicated that ezrin expression was vital for cellular processes such as adhesive and invasive activity. SIGNIFICANCE: High ezrin expression indicates an adverse prognosis in primary CAV and CRLM.
Kadaba R, Birke H, Wang J, et al., 2013, Imbalance of desmoplastic stromal cell numbers drives aggressive cancer processes., J Pathol, Vol: 230, Pages: 107-117
Epithelial tissues have sparse stroma, in contrast to their corresponding tumours. The effect of cancer cells on stromal cells is well recognized. Increasingly, stromal components, such as endothelial and immune cells, are considered indispensable for cancer progression. The role of desmoplastic stroma, in contrast, is poorly understood. Targeting such cellular components within the tumour is attractive. Recent evidence strongly points towards a dynamic stromal cell participation in cancer progression that impacts patient prognosis. The role of specific desmoplastic stromal cells, such as stellate cells and myofibroblasts in pancreatic, oesophageal and skin cancers, was studied in bio-engineered, physiomimetic organotypic cultures and by regression analysis. For pancreatic cancer, the maximal effect on increasing cancer cell proliferation and invasion, as well as decreasing cancer cell apoptosis, occurs when stromal (pancreatic stellate cells) cells constitute the majority of the cellular population (maximal effect at a stromal cell proportion of 0.66-0.83), accompanied by change in expression of key molecules such as E-cadherin and β-catenin. Gene-expression microarrays, across three tumour types, indicate that stromal cells consistently and significantly alter global cancer cell functions such as cell cycle, cell-cell signalling, cell movement, cell death and inflammatory response. However, these changes are mediated through cancer type-specific alteration of expression, with very few common targets across tumour types. As highlighted by these in vitro data, the reciprocal relationship of E-cadherin and polymeric immunoglobulin receptor (PIGR) expression in cancer cells could be shown, in vivo, to be dependent on the stromal content of human pancreatic cancer. These studies demonstrate that context-specific cancer-stroma crosstalk requires to be precisely defined for effective therapeutic targeting. These data may be relevant to non-malignant processes where
Li NF, Gemenetzidis E, Marshall FJ, et al., 2013, RhoC interacts with integrin α5β1 and enhances its trafficking in migrating pancreatic carcinoma cells., PLoS One, Vol: 8
Human pancreatic ductal adenocarcinoma (PDAC) is characterized by early systemic dissemination. Although RhoC has been implicated in cancer cell migration, the relevant underlying molecular mechanisms remain unknown. RhoC has been implicated in the enhancement of cancer cell migration and invasion, with actions which are distinct from RhoA (84% homology), and are possibly attributed to the divergent C-terminus domain. Here, we confirm that RhoC significantly enhances the migratory and invasive properties of pancreatic carcinoma cells. In addition, we show that RhoC over-expression decreases cancer cell adhesion and, in turn, accelerates cellular body movement and focal adhesion turnover, especially, on fibronectin-coated surfaces. Whilst RhoC over-expression did not alter integrin expression patterns, we show that it enhanced integrin α5β1 internalization and re-cycling (trafficking), an effect that was dependent specifically on the C-terminus (180-193 amino acids) of RhoC protein. We also report that RhoC and integrin α5β1 co-localize within the peri-nuclear region of pancreatic tumor cells, and by masking the CAAX motif at the C-terminal of RhoC protein, we were able to abolish this interaction in vitro and in vivo. Co-localization of integrin α5β1 and RhoC was demonstrable in invading cancer cells in 3D-organotypic cultures, and further mimicked in vivo analyses of, spontaneous human, (two distinct sources: operated patients and rapid autopsy programme) and transgenic murine (LSL-KrasG12D/+;LSL-Trp53R172H/+;Pdx-1-Cre), pancreatic cancers. In both cases, co-localization of integrin α5β1 and RhoC correlated with poor differentiation status and metastatic potential. We propose that RhoC facilitates tumor cell invasion and promotes subsequent metastasis, in part, by enhancing integrin α5β1 trafficking. Thus, RhoC may serve as a biomarker and a therapeutic target.
Froeling FEM, Feig C, Chelala C, et al., 2011, Retinoic acid-induced pancreatic stellate cell quiescence reduces paracrine Wnt-β-catenin signaling to slow tumor progression., Gastroenterology, Vol: 141, Pages: 1486-1497.14
BACKGROUND & AIMS: Patients with pancreatic ductal adenocarcinoma are deficient in vitamin A, resulting in activation of pancreatic stellate cells (PSCs). We investigated whether restoration of retinol to PSCs restores their quiescence and affects adjacent cancer cells. METHODS: PSCs and cancer cell lines (AsPc1 and Capan1) were exposed to doses and isoforms of retinoic acid (RA) in 2-dimensional and 3-dimensional culture conditions (physiomimetic organotypic culture). The effects of all-trans retinoic acid (ATRA) were studied in LSL-KrasG12D/+;LSL-Trp53R172H/+;Pdx-1-Cre mice, a model of human pancreatic ductal adenocarcinoma. RESULTS: After incubation with ATRA, PSCs were quiescent and had altered expression of genes that regulate proliferation, morphology, and motility; genes that encode cytoskeletal proteins and cytokines; and genes that control other functions, irrespective of culture conditions or dosage. In the organotypic model, and in mice, ATRA induced quiescence of PSCs and thereby reduced cancer cell proliferation and translocation of β-catenin to the nucleus, increased cancer cell apoptosis, and altered tumor morphology. ATRA reduced the motility of PSCs, so these cells created a "wall" at the junction between the tumor and the matrix that prevented cancer cell invasion. Restoring secreted frizzled-related protein 4 (sFRP4) secretion to quiescent PSCs reduced Wnt-β-catenin signaling in cancer cells and their invasive ability. Human primary and metastatic pancreatic tumor tissues stained strongly for cancer cell nuclear β-catenin but had low levels of sFRP4 (in cancer cells and PSCs). CONCLUSIONS: RA induces quiescence and reduces motility of PSCs, leading to reduced proliferation and increased apoptosis of surrounding pancreatic cancer cells. RA isoforms might be developed as therapeutic reagents for pancreatic cancer.
Hariharan D, Constantinides VA, Froeling FEM, et al., 2010, The role of laparoscopy and laparoscopic ultrasound in the preoperative staging of pancreatico-biliary cancers - A meta-analysis, EJSO, Vol: 36, Pages: 941-948, ISSN: 0748-7983
Froeling FEM, Marshall JF, Kocher HM, 2010, Pancreatic cancer organotypic cultures., J Biotechnol, Vol: 148, Pages: 16-23
Pancreatic cancer, the fourth most common cause of cancer-related death, is a devastating disease with poor prognosis. Over the last four decades, no effective new treatments have been developed for this cancer. As a result, its prognosis has remained unchanged. Appropriate cancer models, representing all aspects of pancreatic cancer, will enhance our understanding of its biology. In this review we discuss the evolution and merit of organotypic culture models. These co-culture in vitro systems of cancer and stromal cells grown within, or on top of, reconstituted extracellular matrix gels model pancreatic cancer more realistically than 2D systems. Different methodologies are discussed which enable interrogation of various hypotheses examining the tumour-stroma cross-talk. Thus this validated organotypic culture model provides a system, which can be easily manipulated and used to test (novel) treatment options targeting the cancer, the stromal compartment or both, in a physiologically relevant environment. The big challenge for future research is to expand this model further so that its mimicry of the human tumour is more robust. This will increase our understanding of the biology of this aggressive tumour; ultimately resulting in improved therapies and, therefore, a better prognosis.
Davila S, Froeling FEM, Tan A, et al., 2010, New genetic associations detected in a host response study to hepatitis B vaccine, GENES AND IMMUNITY, Vol: 11, Pages: 232-238, ISSN: 1466-4879
Froeling FEM, Mirza TA, Feakins RM, et al., 2009, Organotypic culture model of pancreatic cancer demonstrates that stromal cells modulate E-cadherin, beta-catenin, and Ezrin expression in tumor cells., Am J Pathol, Vol: 175, Pages: 636-648
Pancreatic cancer is characterized by an intense stromal reaction. Reproducible three-dimensional in vitro systems for exploring interactions of the stroma with pancreatic cancer cells have not previously been available, prompting us to develop such a model. Cancer cells were grown on collagen/Matrigel and embedded with or without stromal cells (hTERT-immortalized human PS-1 stellate cells or MRC-5 fibroblasts) for 7 days. Proliferation and apoptosis, as well as important cell-cell adhesion and cytoskeleton-regulating proteins, were studied. PS-1 cells were confirmed as stellate based on the expression of key cytoskeletal proteins and lipid vesicles. Capan-1, and to a lesser extent PaCa-3, cells differentiated into luminal structures, exhibiting a central apoptotic core with a proliferating peripheral rim and an apico-basal polarity. Presence of either stromal cell type translocated Ezrin from apical (when stromal cells were absent) to basal aspects of cancer cells, where it was associated with invasive activity. Interestingly, the presence of 'normal' (not tumor-derived) stromal cells induced total tumor cell number reduction (P < 0.005) associated with a significant decrease in E-cadherin expression (P < 0.005). Conversely, beta-catenin expression was up-regulated (P < 0.01) in the presence of stromal cells with predominant cytoplasmic expression. Moreover, patient samples confirmed that these data recapitulated the clinical situation. In conclusion, pancreatic organotypic culture offers a reproducible, bio-mimetic, three-dimensional in vitro model that allows examination of the interactions between stromal elements and pancreatic cancer cells.
Kocher HM, Froeling FE, 2008, Chronic pancreatitis., BMJ Clin Evid, Vol: 2008
INTRODUCTION: Chronic pancreatitis affects 3-9 people in 100,000; 70% of cases are alcohol-induced. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of lifestyle interventions in people with chronic pancreatitis? What are the effects of dietary supplements in people with chronic pancreatitis? What are the effects of drug interventions in people with chronic pancreatitis? What are the effects of nerve blocks for pain relief in people with chronic pancreatitis? What are the effects of different invasive treatments for specific complications of chronic pancreatitis? We searched: Medline, Embase, The Cochrane Library, and other important databases up to April 2008 (BMJ Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found 23 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review we present information relating to the effectiveness and safety of the following interventions: avoiding alcohol consumption, biliary decompression, calcium supplements, ductal decompression (endoscopic or surgical), low-fat diet, nerve blocks, opioid analgesics, pancreatic enzyme supplements, pseudocyst decompression (endoscopic or surgical), resection using distal pancreatectomy, resection using pancreaticoduodenectomy (Kausch-Whipple or pylorus-preserving), and vitamin/antioxidant supplements.
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