The contribution of tumorigenic stem cells to haematopoietic cancers has been established for some time, and cells possessing stem-cell properties have been described in several solid tumours. Although chemotherapy kills most cells in a tumour, it is believed to leave tumour stem cells behind, which might be an important mechanism of resistance. For example, the ATP-binding cassette (ABC) drug transporters have been shown to protect cancer stem cells from chemotherapeutic agents. Gaining a better insight into the mechanisms of stem-cell resistance to chemotherapy might therefore lead to new therapeutic targets and better anticancer strategies.

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Tumour stem cells and drug resistance

The Canonical Notch Signaling Pathway: Unfolding the Activation Mechanism

Emerging evidence has suggested that the capability of a tumor to grow and propagate is dependent on a small subset of cells within a tumor, termed cancer stem cells. Although data have been provided to support this theory in human blood, brain, and breast cancers, the identity of pancreatic cancer stem cells has not been determined. Using a xenograft model in which primary human pancreatic adenocarcinomas were grown in immunocompromised mice, we identified a highly tumorigenic subpopulation of pancreatic cancer cells expressing the cell surface markers CD44, CD24, and epithelial-specific antigen (ESA). Pancreatic cancer cells with the CD44+CD24+ESA+ phenotype (0.2–0.8% of pancreatic cancer cells) had a 100-fold increased tumorigenic potential compared with nontumorigenic cancer cells, with 50% of animals injected with as few as 100 CD44+CD24+ESA+ cells forming tumors that were histologically indistinguishable from the human tumors from which they originated. The enhanced ability of CD44+CD24+ESA+ pancreatic cancer cells to form tumors was confirmed in an orthotopic pancreatic tail injection model. The CD44+CD24+ESA+ pancreatic cancer cells showed the stem cell properties of self-renewal, the ability to produce differentiated progeny, and increased expression of the developmental signaling molecule sonic hedgehog. Identification of pancreatic cancer stem cells and further elucidation of the signaling pathways that regulate their growth and survival may provide novel therapeutic approaches to treat pancreatic cancer, which is notoriously resistant to standard chemotherapy and radiation. [Cancer Res 2007;67(3):1030–7]

https://cancerres.aacrjournals.org/content/canres/67/3/1030.full.pdf

Identification of Pancreatic Cancer Stem Cells

Pancreatic ductal adenocarcinoma (PDA) is among the most lethal human cancers in part because it is insensitive to many chemotherapeutic drugs. Studying a mouse model of PDA that is refractory to the clinically used drug gemcitabine, we found that the tumors in this model were poorly perfused and poorly vascularized, properties that are shared with human PDA. We tested whether the delivery and efficacy of gemcitabine in the mice could be improved by coadministration of IPI-926, a drug that depletes tumor-associated stromal tissue by inhibition of the Hedgehog cellular signaling pathway. The combination therapy produced a transient increase in intratumoral vascular density and intratumoral concentration of gemcitabine, leading to transient stabilization of disease. Thus, inefficient drug delivery may be an important contributor to chemoresistance in pancreatic cancer.

/pdf/inhibition-of-hedgehog-signaling-enhances-delivery-of-4af92tah7e.pdf

Inhibition of Hedgehog Signaling Enhances Delivery of Chemotherapy in a Mouse Model of Pancreatic Cancer

Trp53R172H and KrasG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice

Correlations Between Clinical Activity Indices or Quality of Life Scores to Endoscopic Activity Scores Do not Vary According to Age at Diagnosis, Disease Location, and Disease Behavior in Inflammatory Bowel Disease: 1883

Background: The vascular endothelium maintains tissue-fluid homeostasis by controlling the passage of large molecules and fluid between the blood and interstitial space. The interaction of catenins and the actin cytoskeleton with VE-cadherin (vascular endothelial cadherin) is the primary mechanism for stabilizing AJs (adherens junctions), thereby preventing lung vascular barrier disruption. Members of the Rho (Ras homology) family of GTPases and conventional GEFs (guanine exchange factors) of these GTPases have been demonstrated to play important roles in regulating endothelial permeability. Here, we evaluated the role of DOCK4 (dedicator of cytokinesis 4)—an unconventional Rho family GTPase GEF in vascular function. Methods: We generated mice deficient in DOCK4‚ used DOCK4 silencing and reconstitution approaches in human pulmonary artery endothelial cells‚ used assays to evaluate protein localization, endothelial cell permeability, and small GTPase activation. Results: Our data show that DOCK4-deficient mice are viable. However, these mice have hemorrhage selectively in the lung, incomplete smooth muscle cell coverage in pulmonary vessels, increased basal microvascular permeability, and impaired response to S1P (sphingosine-1-phosphate)–induced reversal of thrombin-induced permeability. Consistent with this, DOCK4 rapidly translocates to the cell periphery and associates with the detergent-insoluble fraction following S1P treatment, and its absence prevents S1P-induced Rac-1 activation and enhancement of barrier function. Moreover, DOCK4-silenced pulmonary artery endothelial cells exhibit enhanced basal permeability in vitro that is associated with enhanced Rho GTPase activation. Conclusions: Our findings indicate that DOCK4 maintains AJs necessary for lung vascular barrier function by establishing the normal balance between RhoA (Ras homolog family member A) and Rac-1–mediated actin cytoskeleton remodeling, a previously unappreciated function for the atypical GEF family of molecules. Our studies also identify S1P as a potential upstream regulator of DOCK4 activity.

DOCK4 Regulation of Rho GTPases Mediates Pulmonary Vascular Barrier Function

Systematic Review and Meta-Analysis: Risk of Colorectal Cancer in Patients of Ulcerative Colitis and an Asian Perspective

Sa1235 PKM2 As a Novel Serum Biomarker of IBD Activity, A Early Pilot Study

https://www.gastrojournal.org/article/S0016-5085(15)32384-2/pdf

Vijay Yajnik

Papers

Correlations Between Clinical Activity Indices or Quality of Life Scores to Endoscopic Activity Scores Do not Vary According to Age at Diagnosis, Disease Location, and Disease Behavior in Inflammatory Bowel Disease: 1883

DOCK4 Regulation of Rho GTPases Mediates Pulmonary Vascular Barrier Function

Systematic Review and Meta-Analysis: Risk of Colorectal Cancer in Patients of Ulcerative Colitis and an Asian Perspective

Sa1235 PKM2 As a Novel Serum Biomarker of IBD Activity, A Early Pilot Study

Mo1754 Early Life Environment Interacts With Genetic Risk in Inflammatory Bowel Diseases