Beta3 integrin modulates transforming growth factor beta induced (TGFBI) function and paclitaxel response in ovarian cancer cells

Cancer Research UK, Cambridge Research Institute, Robinson Way, Cambridge, CB2 0RE, United Kingdom. .
Molecular Cancer (Impact Factor: 4.26). 05/2012; 11(1):36. DOI: 10.1186/1476-4598-11-36
Source: PubMed

ABSTRACT The extracellular matrix (ECM) has a key role in facilitating the progression of ovarian cancer and we have shown recently that the secreted ECM protein TGFBI modulates the response of ovarian cancer to paclitaxel-induced cell death.
We have determined TGFBI signaling from the extracellular environment is preferential for the cell surface αvß3 integrin heterodimer, in contrast to periostin, a TGFBI paralogue, which signals primarily via a ß1 integrin-mediated pathway. We demonstrate that suppression of ß1 integrin expression, in ß3 integrin-expressing ovarian cancer cells, increases adhesion to rTGFBI. In addition, Syndecan-1 and -4 expression is dispensable for adhesion to rTGFBI and loss of Syndecan-1 cooperates with the loss of ß1 integrin to further enhance adhesion to rTGFBI. The RGD motif present in the carboxy-terminus of TGFBI is necessary, but not sufficient, for SKOV3 cell adhesion and is dispensable for adhesion of ovarian cancer cells lacking ß3 integrin expression. In contrast to TGFBI, the carboxy-terminus of periostin, lacking a RGD motif, is unable to support adhesion of ovarian cancer cells. Suppression of ß3 integrin in SKOV3 cells increases resistance to paclitaxel-induced cell death while suppression of ß1 integrin has no effect. Furthermore, suppression of TGFBI expression stimulates a paclitaxel resistant phenotype while suppression of fibronectin expression, which primarily signals through a ß1 integrin-mediated pathway, increases paclitaxel sensitivity.
Therefore, different ECM components use distinct signaling mechanisms in ovarian cancer cells and in particular, TGFBI preferentially interacts through a ß3 integrin receptor mediated mechanism to regulate the response of cells to paclitaxel-induced cell death.

Download full-text


Available from: David A. Tumbarello, May 29, 2014
1 Follower
32 Reads
  • Source
    • "While marker identification and development in ovarian cancer is generally limited to early detection, monitoring progression, or detecting recurrence, there are some encouraging preliminary studies linking markers with drug response, thereby demonstrating early potential for informing effective individualized chemotherapy selection. For example, expression of Copper importers/exporters, ERCC1, Tau, GST-Pi, MLH1, and XIAP, and mutations of MLH1, BRCA1/BRCA2, and p53 have been linked to platinum response, and expression of TGFBI, Survivin, and mutation of tubulin are associated with response to paclitaxel [8–21]. However, none of these biomarkers have demonstrated sufficient clinical validation required to inform clinical treatment decisions. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The objective of this review is to summarize recent scientific and medical literature regarding chemoresponse assays or chemotherapy sensitivity and resistance assays (CSRAs), specifically as applied to epithelial ovarian cancer. A total of sixty-seven articles, identified through PubMed using the key words "in vitro chemoresponse assay," "chemo sensitivity resistance assay," "ATP," "HDRA," "EDR," "MiCK," and "ChemoFx," were reviewed. Recent publications on marker validation, including relevant clinical trial designs, were also included. Recent CSRA research and clinical studies are outlined in this review. Published findings demonstrate benefits regarding patient outcome with respect to recent CSRAs. Specifically, analytical and clinical validations, as well as clinical utility and economic benefit, of the most common clinically used CSRA in the United States support its use to aid in making effective, individualized clinical treatment selections for patients with ovarian cancer.
    Clinical and Translational Oncology 07/2014; 16(9). DOI:10.1007/s12094-014-1192-8 · 2.08 Impact Factor
  • Source
    • "Interestingly, several reports have shown TgfβI expression is necessary for sensitivity to cytotoxic drugs [31], [32], [33], [34], and synergistic drug interaction correlates with its expression [35]. These effects seem to be primarily mediated through activation of integrin pathways, but mTor activation may also play a role [32], [36], [37], [38]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Triple-negative breast cancers are associated with poor clinical outcomes and new therapeutic strategies are clearly needed. Gallotannin (Gltn) has been previously demonstrated to have potent anti-tumor properties against cholangiocarcinoma in mice, but little is known regarding its capacity to suppress tumor outgrowth in breast cancer models. We tested Gltn for potential growth inhibitory properties against a variety of breast cancer cell lines in vitro. In particular, triple-negative breast cancer cells display higher levels of sensitivity to Gltn. The loss of proliferative capacity in Gltn exposed cells is associated with slowed cell cycle progression and S phase arrest, dependent on Chk2 phosphorylation and further characterized by changes to proliferation related genes, such as cyclin D1 (CcnD1) as determined by Nanostring technology. Importantly, Gltn administered orally or via intraperitoneal (IP) injections greatly reduced tumor outgrowth of triple-negative breast cells from mammary fat pads without signs of toxicity. In conclusion, these data strongly suggest that Gltn represents a novel approach to treat triple-negative breast carcinomas.
    PLoS ONE 03/2014; 9(3):e92853. DOI:10.1371/journal.pone.0092853 · 3.23 Impact Factor
  • Source
    • "Paclitaxel-resistant cells treated with recombinant βig-H3 protein show integrin-dependent restoration of paclitaxel sensitivity via FAK- and Rho-dependent stabilization of microtubules [86]. More recent studies have also shown that the suppression of β3 integrin and βig-H3 increase the resistance of SKOV3 to paclitaxel [87]. A strong association between elevated βig-H3 expression and the response to chemotherapy has also been identified in lung cancer patients [96]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Transforming growth factor-beta-induced protein (TGFBI, also known as βig-H3 and keratoepithelin) is an extracellular matrix protein that plays a role in a wide range of physiological and pathological conditions including diabetes, corneal dystrophy and tumorigenesis. Many reports indicate that βig-H3 functions as a tumor suppressor. Loss of βig-H3 expression has been described in several cancers including ovarian cancer and promoter hypermethylation has been identified as an important mechanism for the silencing of the TGFBI gene. Our recent findings that βig-H3 is down-regulated in ovarian cancer and that high concentrations of βig-H3 can induce ovarian cancer cell death support a tumor suppressor role. However, there is also convincing data in the literature reporting a tumor-promoting role for βig-H3. We have shown βig-H3 to be abundantly expressed by peritoneal cells and increase the metastatic potential of ovarian cancer cells by promoting cell motility, invasion, and adhesion to peritoneal cells. Our findings suggest that βig-H3 has dual functions and can act both as a tumor suppressor or tumor promoter depending on the tumor microenvironment. This article reviews the current understanding of βig-H3 function in cancer cells with particular focus on ovarian cancer.
    International Journal of Molecular Sciences 12/2012; 13(8):10461-77. DOI:10.3390/ijms130810461 · 2.86 Impact Factor
Show more