Fieke Froeling

New genetic associations detected in a host response study to hepatitis B vaccine

The immune response to hepatitis B vaccination differs greatly among individuals, with 5–10% of healthy people failing to produce protective levels of antibodies. Several factors have been implicated in determining this response, chiefly individual genetic variation and age. Aiming to identify genes involved in the response to hepatitis B vaccination, a two-stage investigation of 6091 single-nucleotide polymorphisms (SNPs) in 914 immune genes was performed in an Indonesian cohort of 981 individuals showing normal levels of anti-HBs versus 665 individuals displaying undetectable levels of anti-HBs 18 months after initial dose of the vaccine. Of 275 SNPs identified in the first stage (476 normal/372 nonresponders) with P<0.05, significant associations were replicated for 25 polymorphisms in 15 genes (503 normal/295 nonresponders). We validated previous findings (HLA-DRA, rs5000563, P-value combined=5.57 × 10−10; OR (95%CI)=0.61 (0.52–0.71)). In addition, we detected a new association outside of the human leukocyte antigen loci region that passed correction for multiple testing. This SNP is in the 3′ downstream region of FOXP1, a transcription factor involved in B-cell development (P-value combined=9.2 × 10−6; OR (95%CI)=1.38 (1.2–1.6)).These findings might help to understand the biological reasons behind vaccine failure and other aspects of variation in the immune responses of healthy individuals.

Imbalance of desmoplastic stromal cell numbers drives aggressive cancer processes

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 epithelial cells interact with stromal cells, such as chronic inflammatory and fibrotic conditions. Copyright

Pancreatic cancer organotypic cultures.

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.

Gestational Trophoblastic Tumours: An Update for 2014

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.

RhoC Interacts with Integrin α5β1 and Enhances Its Trafficking in Migrating Pancreatic Carcinoma Cells

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.

Homeostatic Restoration of Desmoplastic Stroma Rather Than Its Ablation Slows Pancreatic Cancer Progression

STAFF OF CONTRIBUTORS Joseph Anderson, White River Junction, VT Darren M. Brenner, Chicago, IL Andrew T. Chan, Boston, MA Francis K. L. Chan, Hong Kong, China Massimo Colombo, Milan, Italy Gregory A. Cote, Charleston, SC B. Joseph Elmunzer, Charleston, SC Alex Ford, Leeds, United Kingdom Timothy B. Gardner, Lebanon, NH Lauren B. Gerson, San Francisco, CA Michelle Kang Kim, New York, NY W. Ray Kim, Rochester, MN Paul Y. Kwo, Indianapolis, IN Edward V. Loftus, Rochester, MN Uma Mahadevan, San Francisco, CA Laurent Peyrin-Biroulet, Vandoeuvre-lès-Nancy, France Mark Pimentel, Los Angeles, CA Jesus Rivera-Nieves, San Diego, CA Joel H. Rubenstein, Ann Arbor, MI Sameer Saini, Ann Arbor, MI Ekihiro Seki, La Jolla, CA Shamita B. Shah, Stanford, CA Pratima Sharma, Ann Arbor, MI Amit Singal, Dallas, TX Jan Tack, Leuven, Belgium Akbar Waljee, Ann Arbor, MI Alastair J. M. Watson, Norwich, United Kingdom

Pancreatic cancer foiled by a switch of tumour subtype

Mutations in the gene KDM6A drive an aggressive subtype of pancreatic cancer by causing repositioning of an enzyme complex that modifies histone proteins associated with DNA, leading to altered gene expression.Mutations in the gene KDM6A drive an aggressive subtype of pancreatic cancer by causing repositioning of an enzyme complex that modifies histone proteins associated with DNA, leading to altered gene expression.