Colon cancer through the looking glass

Inaugural lecture by prof.dr. James Hardwick on the acceptance of his position as professor of Gastroenterology and Hepathology, in particular the Early Detection and Treatment of Colorectal Tumours at the Universiteit Leiden on Friday September 18, 2015  Inaugural lecture by prof.dr. James Hardwick on the acceptance of his position as professor of Gastroenterology and Hepathology, in particular the Early Detection and Treatment of Colorectal Tumours at the Universiteit Leiden on Friday September 18, 201

Putting the Wnt up colon cancer

Cellular mechanisms in basic and clinical gastroenterology and hepatolog

Extracellular BMP Antagonists, Multifaceted Orchestrators in the Tumor and Its Microenvironment

The bone morphogenetic proteins (BMPs), a subgroup of the transforming growth factor-beta (TGF-beta) superfamily, are involved in multiple biological processes such as embryonic development and maintenance of adult tissue homeostasis. The importance of a functional BMP pathway is underlined by various diseases, including cancer, which can arise as a consequence of dysregulated BMP signaling. Mutations in crucial elements of this signaling pathway, such as receptors, have been reported to disrupt BMP signaling. Next to that, aberrant expression of BMP antagonists could also contribute to abrogated signaling. In this review we set out to highlight how BMP antagonists affect not only the cancer cells, but also the other cells present in the microenvironment to influence cancer progression.Cellular mechanisms in basic and clinical gastroenterology and hepatolog

Luminescence-based Imaging Approaches in the Field of Interventional Molecular Imaging

Cellular mechanisms in basic and clinical gastroenterology and hepatolog

Safety of endoscopic mucosal resection (EMR) of large non-pedunculated colorectal adenomas in the elderly

Cellular mechanisms in basic and clinical gastroenterology and hepatolog

Endoglin targeting inhibits tumor angiogenesis and metastatic spread in breast cancer

Endoglin, a transforming growth factor-beta co-receptor, is highly expressed on angiogenic endothelial cells in solid tumors. Therefore, targeting endoglin is currently being explored in clinical trials for anti-angiogenic therapy. In this project, the redundancy between endoglin and vascular endothelial growth factor (VEGF) signaling in angiogenesis and the effects of targeting both pathways on breast cancer metastasis were explored. In patient samples, increased endoglin signaling after VEGF inhibition was observed. In vitro TRC105, an endoglin-neutralizing antibody, increased VEGF signaling in endothelial cells. Moreover, combined targeting of the endoglin and VEGF pathway, with the VEGF receptor kinase inhibitor SU5416, increased antiangiogenic effects in vitro and in a zebrafish angiogenesis model. Next, in a mouse model for invasive lobular breast cancer, the effects of TRC105 and SU5416 on tumor growth and metastasis were explored. Although TRC105 and SU5416 decreased tumor vascular density, tumor volume was unaffected. Strikingly, in mice treated with TRC105, or TRC105 and SU5416 combined, a strong inhibition in the number of metastases was seen. Moreover, upon resection of the primary tumor, strong inhibition of metastatic spread by TRC105 was observed in an adjuvant setting. To confirm these data, we assessed the effects of endoglin-Fc (an endoglin ligand trap) on metastasis formation. Similar to treatment with TRC105 in the resection model, endoglin-Fc-expressing tumors showed strong inhibition of distant metastases. These results show, for the first time, that targeting endoglin, either with neutralizing antibodies or a ligand trap, strongly inhibits metastatic spread of breast cancer in vivo.Surgical oncolog

Intraoperative fluorescence imaging to localize tumors and sentinel lymph nodes in rectal cancer

Surgical oncolog

Transcriptomic and immunophenotypic profiling reveals molecular and immunological hallmarks of colorectal cancer tumourigenesis

ObjectiveBiological insights into the stepwise development and progression of colorectal cancer (CRC) are imperative to develop tailored approaches for early detection and optimal clinical management of this disease. Here, we aimed to dissect the transcriptional and immunologic alterations that accompany malignant transformation in CRC and to identify clinically relevant biomarkers through spatial profiling of pT1 CRC samples. DesignWe employed digital spatial profiling (GeoMx) on eight pT1 CRCs to study gene expression in the epithelial and stromal segments across regions of distinct histology, including normal mucosa, low-grade and high-grade dysplasia and cancer. Consecutive histology sections were profiled by imaging mass cytometry to reveal immune contextures. Finally, publicly available single-cell RNA-sequencing data was analysed to determine the cellular origin of relevant transcripts. ResultsComparison of gene expression between regions within pT1 CRC samples identified differentially expressed genes in the epithelium (n=1394 genes) and the stromal segments (n=1145 genes) across distinct histologies. Pathway analysis identified an early onset of inflammatory responses during malignant transformation, typified by upregulation of gene signatures such as innate immune sensing. We detected increased infiltration of myeloid cells and a shift in macrophage populations from pro-inflammatory HLA-DR(+)CD204(-) macrophages to HLA-DR(-)CD204(+) immune-suppressive subsets from normal tissue through dysplasia to cancer, accompanied by the upregulation of the CD47/SIRP alpha 'don't eat me signal'. ConclusionSpatial profiling revealed the molecular and immunological landscape of CRC tumourigenesis at early disease stage. We identified biomarkers with strong association with disease progression as well as targetable immune processes that are exploitable in a clinical setting.Cellular mechanisms in basic and clinical gastroenterology and hepatolog

Influence of Combination Therapy with Immune Modulators on Anti-TNF Trough Levels and Antibodies in Patients with IBD

Cellular mechanisms in basic and clinical gastroenterology and hepatolog