Cancer‐associated fibroblasts (CAFs) constitute a major compartment of the tumor microenvironment. In the present study, we investigated the role for CAFs in breast cancer progression and underlying molecular mechanisms. Human breast cancer MDA‐MB‐231 cells treated with the CAF‐conditioned media manifested a more proliferative phenotype, as evidenced by enhanced messenger RNA (mRNA) expression of Cyclin D1, c‐Myc, and proliferating cell nuclear antigen. Analysis of data from The Cancer Genome Atlas revealed that fibroblast growth factor‐2 (FGF2) expression was well correlated with the presence of CAFs. We noticed that the mRNA level of FGF2 in CAFs was higher than that in normal fibroblasts. FGF2 exerts its biological effects through interaction with FGF receptor 1 (FGFR1). In the breast cancer tissue array, 42% estrogen receptor‐negative patients coexpressed FGF2 and FGFR1, whereas only 19% estrogen receptor‐positive patients exhibited coexpression. CAF‐stimulated MDA‐MB‐231 cell migration and invasiveness were abolished when FGF2‐neutralizing antibody was added to the conditioned media of CAFs. In a xenograft mouse model, coinjection of MDA‐MB‐231 cells with activated fibroblasts expressing FGF2 dramatically enhanced tumor growth, and this was abrogated by silencing of FGFR1 in cancer cells. In addition, treatment of MDA‐MB‐231 cells with FGF2 enhanced expression of Cyclin D1, a key molecule involved in cell cycle progression. FGF2‐induced cell migration and upregulation of Cyclin D1 were abolished by siRNA‐mediated FGFR1 silencing. Taken together, the above findings suggest that CAFs promote growth, migration and invasion of MDA‐MB‐231 cells via the paracrine FGF2‐FGFR1 loop in the breast tumor microenvironment.
1. Zinc acexamate (ZAC) is ionized to zinc and epsilon-acetamidocaproic acid (AACA). Thus, the pharmacokinetics and tissue distribution of zinc and AACA after intravenous (50 mg kg(-1)) and oral (100 mg kg(-1)) administration of ZAC were evaluated in rats. Also the pharmacokinetics of AACA after intravenous (10, 20, 30, and 50 mg kg(-1)) and oral (20, 50, and 100 mg kg(-1)) administration of ZAC and the first-pass extractions of AACA at a ZAC dose of 20 mg kg(-1) were evaluated in rats. 2. After oral administration of ZAC (20 mg kg(-1)), approximately 0.408% of the oral dose was not absorbed, the F value was approximately 47.1%, and the hepatic and gastrointestinal (GI) first-pass extractions of AACA were approximately 8.50% and 46.4% of the oral dose, respectively. The incomplete F value of AACA was mainly due to the considerable GI first-pass extraction in rats. 3. Affinity of rat tissues to zinc and AACA was low-the tissue-to-plasma (T/P) ratios were less than unity. The equilibrium plasma-to-blood cells partition ratios of AACA were independent of initial blood ZAC concentrations of 1, 5, and 10 microg ml(-1)-the mean values were 0.481, 0.490, and 0.499, respectively. The bound fractions of zinc and AACA to rat plasma were 96.6% and 39.0%, respectively.
The tumor suppressor phosphatase and tensin homologue (PTEN) has phosphatase activity, with phosphatidylinositol (3,4,5)-trisphosphate (PIP3), a product of phosphatidylinositol 3-kinase (PI3K), as one of the principal substrates. PTEN is a negative regulator of the Akt pathway, which plays a fundamental role in controlling cell growth, survival, and proliferation. Loss of PTEN function has been observed in many different types of cancer. Functional inactivation of PTEN as a consequence of germ-line mutations or promoter hypermethylation predisposes individuals to malignancies. PTEN undergoes posttranslational modifications, such as oxidation, acetylation, phosphorylation, SUMOylation, and ubiquitination, which influence its catalytic activity, interactions with other proteins, and subcellular localization. Cellular redox status is crucial for posttranslational modification of PTEN and its functional consequences. Oxidative stress and inflammation are major causes of loss of PTEN function. Pharmacologic or nutritional restoration of PTEN function is considered a reliable strategy in the management of PTEN-defective cancer. In this review, we highlight natural compounds, such as curcumin, indol-3 carbinol, and omega-3 fatty acids, that have the potential to restore or potentiate PTEN expression/activity, thereby suppressing cancer cell proliferation, survival, and resistance to chemotherapeutic agents.
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