Loss of fibulin-5 binding to β1 integrins inhibits tumor growth by increasing the level of ROS

Schluterman, Marie K.; Chapman, Shelby L.; Korpanty, Grzegorz; Ozumi, Kiyoshi; Fukai, Tohru; Yanagisawa, Hiromi; Brekken, Rolf A.

doi:10.1242/jcs.073841

Cited by 14 publications

(24 citation statements)

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“…Our studies reveal that a possible and underappreciated method by which blocking TGF-␤ may reduce tumor burden and metastasis is by inhibiting the synthesis of pro-tumorigenic ECM molecules such as Fbln5. In fact, Fbln5 Ϫ/Ϫ mice exhibited a reduction in metastatic incidence when pancreatic tumors were implanted (26). Along these lines, our in vitro data encourage the analysis of tissues that have been treated with inhibitors of the PI3K/AKT pathway for Fbln5 expression.…”

Section: Discussionsupporting

confidence: 59%

“…6. Fbln5 is a pro-tumorigenic factor in mouse PDA, as Fbln5-deficient and mutant mice show a reduction in pancreatic tumor growth and increased survival (25,26). Fbln5 functions as a tumor promoter in these models by blocking integrin-mediated ROS production.…”

Section: Discussionmentioning

confidence: 99%

“…We have reported that the loss of functional Fbln5 leads to decreased microvessel density specifically in the tumor microenvironment of mouse PDA (26). Furthermore, it has been shown that hypoxia up-regulates Fbln5 in endothelial cells and protects these cells from hypoxiainduced apoptosis (29).…”

Section: Fbln5 Expression In Pancreaticmentioning

confidence: 97%

“…Fbln5 protein levels are increased in mouse PDA compared with a normal pancreas (25). The loss of Fbln5 results in decreased tumor growth in subcutaneous and orthotopic models of PDA (26). Mechanistic studies revealed that Fbln5 blocked FN-mediated integrin-induced ROS production and that the loss of Fbln5 resulted in enhanced ROS production.…”

mentioning

confidence: 99%

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Hypoxia and Transforming Growth Factor β Cooperate to Induce Fibulin-5 Expression in Pancreatic Cancer

Topalovski¹,

Hagopian²,

Wang

et al. 2016

Journal of Biological Chemistry

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The deposition of extracellular matrix (ECM) is a defining feature of pancreatic ductal adenocarcinoma (PDA), where ECM signaling can promote cancer cell survival and epithelial plasticity programs. However, ECM signaling can also limit PDA tumor growth by producing cytotoxic levels of reactive oxygen species. For example, excess fibronectin stimulation of ␣5␤1 integrin on stromal cells in PDA results in reduced angiogenesis and increased tumor cell apoptosis because of oxidative stress. Fibulin-5 (Fbln5) is a matricellular protein that blocks fibronectin-integrin interaction and thus directly limits ECMdriven reactive oxygen species production and supports PDA progression. Compared with normal pancreatic tissue, Fbln5 is expressed abundantly in the stroma of PDA; however, the mechanisms underlying the stimulation of Fbln5 expression in PDA are undefined. Using in vitro and in vivo approaches, we report that hypoxia triggers Fbln5 expression in a TGF-␤-and PI3K-dependent manner. Pharmacologic inhibition of TGF-␤ receptor, PI3K, or protein kinase B (AKT) was found to block hypoxia-induced Fbln5 expression in mouse embryonic fibroblasts and 3T3 fibroblasts. Moreover, tumor-associated fibroblasts from mouse PDA were also responsive to TGF-␤ receptor and PI3K/AKT inhibition with regard to suppression of Fbln5. In genetically engineered mouse models of PDA, therapy-induced hypoxia elevated Fbln5 expression, whereas pharmacologic inhibition of TGF-␤ signaling reduced Fbln5 expression. These findings offer insight into the signaling axis that induces Fbln5 expression in PDA and a potential strategy to block its production.The maintenance of solid tumors relies heavily on cues received from the surrounding environment. The ECM 2 is composed of structural proteins such as FN and collagen, which promote signaling through integrins and receptor tyrosine kinases (1, 2). ECM signaling is modulated by matricellular proteins, which regulate ECM-cell interactions without serving a direct structural function (3-5). The composition of the ECM is dynamic and varies between tumors and tumor types, contributing to intra-and intertumor heterogeneity, which presents challenges for effective therapeutic strategies. Furthermore, mouse studies have revealed anti-and pro-tumorigenic functions for ECM (5-7). In addition to ECM, stromal cells, including endothelial cells, immune cells, and fibroblasts, are present in the tumor microenvironment. These cells contribute to tumor growth, invasion, and chemoresponse (8 -10).During tumor progression, cancer cells release factors that maintain a microenvironment conducive for growth. For example, TGF-␤ is a cytokine expressed in many cancers that enhances the expression of multiple ECM molecules, including but not limited to FN, collagen, elastin, and fibulins (11-13). Fbln5 is a 448-amino acid secretory glycoprotein of the fibulin family of matricellular proteins. Fbln5 is unique among its members as it contains an RGD-integrin binding domain and can ligate a number of integrins (14). Fbln5 is ex...

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Section: Discussionsupporting

confidence: 59%

Section: Discussionmentioning

confidence: 99%

Section: Fbln5 Expression In Pancreaticmentioning

confidence: 97%

mentioning

confidence: 99%

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Hypoxia and Transforming Growth Factor β Cooperate to Induce Fibulin-5 Expression in Pancreatic Cancer

Topalovski¹,

Hagopian²,

Wang

et al. 2016

Journal of Biological Chemistry

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“…Fibulins have been shown to modulate cell morphology, growth, adhesion and motility, and are closely associated with the development of a wide variety of carcinomas (7). As tumor-suppressor genes, fibulin-2 (8,9) and fibulin-5 (10)(11)(12) were widely considered to be associated with the suppression of tumor growth, invasion and angiogenesis. Research findings on the role of fibulin-1 and fibulin-3 in different tumor tissues have been controversial.…”

Section: Introductionmentioning

confidence: 99%

Overexpression of fibulin-4 is associated with tumor progression and poor prognosis in patients with cervical carcinoma

et al. 2014

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Abstract. Fibulin-4, a member of the fibulin family of extracellular glycoproteins, is implicated in the progression of a number of types of cancer. However, the function of fibulin-4 in cervical cancer progression remains unexplored. Fibulin-4 mRNA and protein expression levels in normal cervical tissue, cervical intraepithelial neoplasia (CIN), cervical carcinoma, highly invasive subclones and low-invasive subclones were evaluated by real-time reverse transcriptase-polymerase chain reaction and immunohistochemistry. Serum fibulin-4 levels in patients with CIN and cervical carcinoma were measured by enzyme-linked immunosorbent assay. To assess the angiogenic properties of fibulin-4, vascular endothelial growth factor (VEGF) expression and tumor microvessel density (MVD) were analyzed in the cervical carcinoma cases by immunohistochemistry. Fibulin-4 expression was upregulated in the cervical carcinoma cases, and was positively correlated with MVD and VEGF expression. Fibulin-4 overexpression and high serum levels were significantly associated with advanced stage, low differentiation, lymph node metastasis, and poor prognosis in patients with cervical cancer. Fibulin-4 expression was also found to be overexpressed in highly invasive subclones when compared with the low-invasive subclones. Fibulin-4 is a newly identified glycoprotein that is overexpressed in cervical carcinoma. Fibulin-4 promotes angiogenesis and is associated with poor prognostic clinicopathologic features. This study demonstrated that fibulin-4 may serve as a new prognostic factor and as a potential therapeutic target for patients with cervical carcinoma.

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Possible role of differentially expressing novel protein markers (ligatin and fibulin‐7) in human aqueous humor and trabecular meshwork tissue in glaucoma progression

Basu

Maurya

Kaur

et al. 2019

Cell Biology International

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The pathological mechanism underlying glaucoma has always been a complex aspect of this permanently blinding disease but proteomic studies have been helpful in elucidating it to a great extent in several studies. This study was designed to evaluate the expression and to get an idea about the function of two novel markers (ligatin and fibulin‐7) identified in human aqueous humor (hAH) in relation to glaucomatous progression. A significant increase in the protein content of glaucomatous hAH compared to that of non‐glaucomatous controls (NG‐Ctrls) was observed. Ligatin, fibulin‐7, and its proteolysis were revealed in hAH of primary open angle glaucoma (POAG), primary angle closure glaucoma (PACG) and NG‐Ctrls. Quantification confirmed no significant difference in expression of ligatin, whereas fibulin‐7 was significantly (P < 0.05) low in hAH of PACG in comparison to NG‐Ctrls and POAG. Importantly the immunohistochemical assay for both indicated their possible involvement in the maintenance of the appropriate structure of TM in vivo. Since oxidative stress is a major contributor to glaucomatous pathogenesis, in vitro analysis of nuclear and cytoplasmic fractions indicated intracellular changes in localization and expression of ligatin upon oxidative insult of human trabecular meshwork (TM) cells. While no such changes were found for fibulin‐7 expression. This was also corroborated with the immunocytochemical assay. Though a study with a small sample size, this is the first report which confirms the presence of ligatin and fibulin‐7 in hAH, quantified their differential expression, and indicated the possibility of their involvement in the maintenance of the TM structure.

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Loss of fibulin-5 binding to β1 integrins inhibits tumor growth by increasing the level of ROS

Cited by 14 publications

References 1 publication

Hypoxia and Transforming Growth Factor β Cooperate to Induce Fibulin-5 Expression in Pancreatic Cancer

Hypoxia and Transforming Growth Factor β Cooperate to Induce Fibulin-5 Expression in Pancreatic Cancer

Overexpression of fibulin-4 is associated with tumor progression and poor prognosis in patients with cervical carcinoma

Possible role of differentially expressing novel protein markers (ligatin and fibulin‐7) in human aqueous humor and trabecular meshwork tissue in glaucoma progression

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