Anterior Gradient 2 (AGR2) is a protein disulfide isomerase that plays important roles in diverse processes in multiple cell lineages as a developmental regulator, survival factor and susceptibility gene for inflammatory bowel disease. Here, we show using germline and inducible Agr2−/− mice that Agr2 plays important roles in intestinal homeostasis. Agr2−/− intestine has decreased goblet cell Mucin 2, dramatic expansion of the Paneth cell compartment, abnormal Paneth cell localization, elevated endoplasmic reticulum (ER) stress, severe terminal ileitis and colitis. Cell culture experiments show that Agr2 expression is induced by ER stress, and that siRNA knockdown of Agr2 increases ER stress response. These studies implicate Agr2 in intestinal homeostasis and ER stress and suggest a role in the etiology of inflammatory bowel disease.

Sporadic human mismatch repair (MMR)-deficient colorectal cancers account for f12.5% of all cases of colorectal cancer. MMR-deficient colorectal cancers are classically characterized by right-sided location, multifocality, mucinous histology, and lymphocytic infiltration. However, tumors in germ-line MMRdeficient mouse models lack these histopathologic features.

BackgroundDecades of cytotoxic and more recently immunotherapy treatments for malignant glioma have had limited success due to dynamic intra-tumoral heterogeneity. The dynamic interplay of cancer cell subpopulations has been found to be under the control of proteins in the cancer microenvironment. EGF-containing fibulin-like extracellular matrix protein (EFEMP1) (also fibulin-3) has the multiple functions of suppressing cancer growth and angiogenesis, while promoting cancer cell invasion. EFEMP1-derived tumor suppressor protein (ETSP) retains EFEMP1’s anti-growth and anti-angiogenic functions while actually inhibiting cancer cell invasion.MethodsIn this study, we examined the therapeutic effect on glioblastoma multiforme (GBM) of an in vitro synthesized protein, ZR30, which is based on the sequence of ETSP, excluding the signaling peptide.ResultsZR30 showed the same effects as ETSP in blocking EGFR/NOTCH/AKT signaling pathways, when applied to cultures of multiple GBM cell lines and primary cultures. ZR30’s inhibition of MMP2 activation was shown not only for GBM cells, but also for other types of cancer cells having overexpression of MMP2. A significant improvement in survival of mice with orthotopic human GBM xenografts was observed after a single, intra-tumoral injection of ZR30. Using a model mimicking the intra-tumoral heterogeneity of GBM with cell subpopulations carrying different invasive and proliferative phenotypes, we demonstrated an equal and simultaneous tumor suppressive effect of ZR30 on both tumor cell subpopulations, with suppression of FOXM1 and activation of SEMA3B expressions in the xenografts.ConclusionOverall, the data support a complementary pleiotrophic therapeutic effect of ZR30 acting in the extracellular compartment of GBM.

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Aim: Current cancer treatments are challenged by the plasticity of cancer cells, largely influenced by chromosomal instability (CIN) leading to variations in karyotype known as tumor-specific aneuploidy, which in turn, leads to intratumor cellular heterogeneity (TH). Cells with certain chromosomal defects often survive treatment and the growthassociated states of TH persist in recurrent tumors. Modulation of the CIN rate seems to reside within the tumor itself.In an attempt to develop a therapy targeting cancer plasticity, we studied the possible extracellular control of CIN rate in Chr7-defined TH in gliomas.Methods: Chr7-fluorescence in situ hybridization was applied on various grades of gliomas, in vitro cultures and intracranial xenografts of two syngeneic glioma lines (U251 and U251-NS) derived from various cell-inoculating densities, with or without EFEMP1 overexpression. Results:A grade-dependent increase of trisomy-7 population and Chr7-defined cell diversity was shown in gliomas. A negative association between Chr7-MS rate and initial cell-inoculating density was observed which was prevented by EFEMP1 overexpression. Conclusion:Our data demonstrate that CIN is a major driver for cancer cell plasticity and suggest that CIN can be controlled by extracellular factors derived from normal and tumor cells, and EFEMP1 is one of these factors.