SUMMARY Thrombospondin (Thbs) proteins are induced in sites of tissue damage or active remodeling. The endoplasmic reticulum (ER) stress response is also prominently induced with disease where it regulates protein production and resolution of misfolded proteins. Here we describe a novel function for Thbs’ as ER resident effectors of an adaptive ER stress response. Thbs4 cardiac-specific transgenic mice were protected from myocardial injury while Thbs4−/− mice were sensitized to cardiac maladaptation. Thbs induction produced a unique profile of adaptive ER stress response factors and expansion of the ER and downstream vesicles. The type-3 repeat domain in Thbs’ bind the ER luminal domain of activating transcription factor 6α (Atf6α) to promote its nuclear shuttling. Thbs4−/−mice failed to show activation of Atf6α and other ER stress response factors with injury, and Thbs4-mediated protection was lost when Atf6α was deleted. Hence, Thbs’ can function inside the cell during disease/remodeling to augment ER function and protect through a mechanism involving regulation of Atf6α.

The post-myocardial infarction wound repair process involves temporarily overlapping phases that include inflammation, formation of granulation tissue, scar formation, and overall left ventricle (LV) remodelling. The myocardial extracellular matrix (ECM) plays an important role in maintaining the structural and functional integrity of the heart and is centrally involved in wound repair post-myocardial infarction (MI). The main proteolytic system involved in the degradation of the ECM in the heart is the matrix metalloproteinase (MMPs) system. The present review will focus on the importance of the unique temporal and spatial window of MMPs and their inhibitors (TIMPs) within the different wound healing phases post-MI. It summarizes (1) the MMP/TIMP levels at different time points post-MI, (2) the alterations seen in post-MI healing in genetically modified mice, and (3) the effects and limitations of therapeutic MMP-inhibition post-MI.

No abstract

The transforming and tumor growthpromoting properties of Axl, a member of the Tyro3, Axl, and Mer (TAM) family of receptor tyrosine kinases (TAMRs), are well recognized. In contrast, little is known about the role of the TAMR ligand growth arrest-specific gene 6 (Gas6) in tumor biology. By using Gas6-deficient (Gas6 ؊/؊ ) mice, we show that bone marrow-derived Gas6 promotes growth and metastasis in different experimental cancer models, including one resistant to vascular endothelial growth factor inhibitors. Mechanistic studies reveal that circulating leukocytes produce minimal Gas6. However, once infiltrated in the tumor, leukocytes upregulate Gas6, which is mitogenic for tumor cells. Consistent herewith, impaired tumor growth in Gas6 ؊/؊ mice is rescued by transplantation of wild-type bone marrow and, conversely, mimicked by transplantation of Gas6 ؊/؊ bone marrow into wild-type hosts. These findings highlight a novel role for Gas6 in a positive amplification loop, whereby tumors promote their growth by educating infiltrating leukocytes to up-regulate the production of the mitogen Gas6. Hence, inhibition of Gas6 might offer novel opportunities for the treatment of cancer. IntroductionGrowth arrest-specific gene 6 (Gas6) was discovered because its expression is up-regulated in fibroblasts under growth-arrest conditions. 1,2 This factor exerts pleiotropic functions in health and disease: it amplifies platelet aggregation during thrombus formation, 3,4 enhances erythropoiesis, 5 and increases leukocyte extravasation in inflammatory conditions, 6 among other functions. 7,8 Gas6 binds to the Tyro3, Axl, and Mer (TAM) family of receptor tyrosine kinases (TAMRs), which consists of Tyro3 (Sky/Rse), Axl (Ufo/ Ark), and Mer (Eyk), although the binding affinity of this ligand differs for each receptor (AxlϾTyro3Ͼ ϾMer). 9,10 TAMRs, in particular Axl, have transforming properties. Indeed, overexpression of a truncated version of Axl in premalignant cells is sufficient to induce tumors in mice. 11 Axl is also highly expressed in human tumor cells in vitro, [12][13][14][15] as well as in a large variety of primary human cancers, including leukemia, 16 gastric cancer, 17 colon cancer, 18 breast cancer, 19 ovarian cancer, 20 and glioblastoma, 21 among others. In gastric cancer, Axl expression is associated with lymph node metastasis, an adverse prognostic factor. 17 However, little is known about the role of Gas6 in cancer. Gas6 is overexpressed in human ovarian, endometrial, gastric, thyroid, and glioblastoma tumors. 17,[20][21][22][23] In those studies, expression of Gas6 was detected in tumor cells, endothelial cells, and astrocytes, 20-24 but expression of Gas6 in tumor-infiltrated leukocytes has not been studied. Gas6 promotes proliferation and survival of different cancer cell lines, including prostate and melanoma tumor cells. 13,14 Interestingly, when glioma tumors coexpress high levels of Axl and Gas6, the survival of cancer patients is shortened. 21 Inhibition of Gas6 by a soluble Axl trap in vitro or a dominantneg...