LTBP3 promotes early metastatic events during cancer cell dissemination.

Latent transforming growth factor ß (TGFß)-binding proteins (LTBPs) are important for the secretion, activation, and function of mature TGFß, especially so in cancer cell physiology. However, specific roles of the LTBPs remain understudied in the context of the primary tumor microenvironment. Herein, we investigated the role of LTBP3 in the distinct processes involved in cancer metastasis. By using three human tumor cell lines of different tissue origin (epidermoid HEp-3 and prostate PC-3 carcinomas and HT-1080 fibrosarcoma) and several metastasis models conducted in both mammalian and avian settings, we show that LTBP3 is involved in the early dissemination of primary cancer cells, namely in the intravasation step of the metastatic cascade. Knockdown of LTBP3 in all tested cell lines led to significant inhibition of tumor cell intravasation, but did not affect primary tumor growth. LTBP3 was dispensable in the late steps of carcinoma cell metastasis that follow tumor cell intravasation, including vascular arrest, extravasation, and tissue colonization. However, LTBP3 depletion diminished the angiogenesis-inducing potential of HEp-3 cells in vivo, which was restorable by exogenous delivery of LTBP3 protein. A similar compensatory approach rescued the dampened intravasation of LTBP3-deficient HEp-3 cells, suggesting that LTBP3 regulates the induction of the intravasation-supporting angiogenic vasculature within developing primary tumors. Using our recently developed microtumor model, we confirmed that LTBP3 loss resulted in the development of intratumoral vessels with an abnormal microarchitecture incompatible with efficient intravasation of HEp-3 carcinoma cells. Collectively, these findings demonstrate that LTBP3 represents a novel oncotarget that has distinctive functions in the regulation of angiogenesis-dependent tumor cell intravasation, a critical process during early cancer dissemination. Our experimental data are also consistent with the survival prognostic value of LTBP3 expression in early-stage head and neck squamous cell carcinomas, further indicating a specific role for LTBP3 in cancer progression toward metastatic disease.

Racial differences in disease phenotypes in patients with Crohn's disease.

BACKGROUND: Our objectives were to assess the differences in perforating disease behavior, disease severity, and extraintestinal manifestations (EIM) in patients with Crohn's disease (CD) by race. MATERIALS AND METHODS: We identified outpatients with CD evaluated at the University of Maryland Gastroenterology Faculty Practice office or the Baltimore Veterans Affairs Maryland Health Care System, from 1997 to 2005. We assessed age at diagnosis, disease behavior, disease location, need for surgery and EIM. RESULTS: Race was not associated with perforating disease behavior (relative risk [RR] 0.79, 95% confidence interval [CI] 0.46-1.35), need for surgery (RR 0.89, 95% CI 0.56-1.12), and EIM of CD (RR 0.77, 95% CI 0.46-1.27). White patients were significantly more likely to have ileal disease, whereas African American patients were significantly more likely to have ileocolonic and colonic disease. Age at diagnosis younger than 40 years (odds ratio [OR] 4.41, 95% CI 1.84-10.56) and ileocolonic disease (OR 2.39, 95% CI 1.24-4.63) were independent risk factors for perforating disease behavior. Similarly, age at diagnosis younger than 40 (OR 2.79, 95% CI 1.45-5.33), ileal disease (OR 3.76, 95% CI 1.66-8.48), and ileocolonic disease (OR 2.57, 95% CI1.21-5.46) were associated with the need for surgery. Female gender (OR 4.23, 95% CI 1.87-9.58) and a positive family history of CD (OR 3.45, 95% CI 1.49-8.0) were associated with joint manifestations of CD. DISCUSSION: We did not detect differences in disease behavior, severity, or joint EIM by race. Although African American patients were more likely to have ileocolonic or colonic disease, these factors did not affect disease behavior or severity.