Direct Involvement of Breast Tumor Fibroblasts in the Modulation of Tamoxifen Sensitivity

Shekhar, Malathy P.V.; Santner, Steven J.; Carolin, Kathryn A; Tait, Larry

doi:10.2353/ajpath.2007.061004

Cited by 92 publications

(82 citation statements)

References 51 publications

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“…In 1990, Teicher and colleagues proposed that something other than the inherent properties of tumor cells must affect the ability of these cells to resist cytotoxic drugs (38). Since then, several studies have shown that fibroblasts can induce resistance to various anticancer treatments, such as tamoxifen in the treatment of breast cancer (28,39), gemcitabine and radiotherapy in the treatment of pancreatic adenocarcinoma (26), and paclitaxel in the treatment of non-small cell lung cancer (30). Conversely, fibroblasts may also sensitize tumor cells to therapy as was shown for RAF and MEK1 inhibitors in breast cancer (33).…”

Section: Discussionmentioning

confidence: 99%

“…CAFs provide protumorigenic signals that lead to increased tumor growth via the stimulation of tumor cell proliferation and angiogenesis as well as the formation of metastases by the enhancement of the migratory and invasive potential of the tumor cells (18)(19)(20)(21)(22)(23)(24)(25). As a number of publications suggest that CAFs could also modulate the drug sensitivity of cancer cells (26)(27)(28)(29)(30)(31)(32)(33)(34), this study was undertaken to evaluate the influence of CAFs on the cetuximab response in HNSCC cell lines.…”

Section: Introductionmentioning

confidence: 99%

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Cancer-Associated Fibroblasts Induce Matrix Metalloproteinase–Mediated Cetuximab Resistance in Head and Neck Squamous Cell Carcinoma Cells

Johansson

Ansell

Jerhammar

et al. 2012

Molecular Cancer Research

103

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A growing body of evidence suggests that components of the tumor microenvironment, including cancer-associated fibroblasts (CAF), may modulate the treatment sensitivity of tumor cells. Here, we investigated the possible influence of CAFs on the sensitivity of head and neck squamous cell carcinoma (HNSCC) cell lines to cetuximab, an antagonistic epidermal growth factor receptor (EGFR) antibody. Cetuximab treatment caused a reduction in the proliferation rate of HNSCC cell lines, whereas the growth of HNSCC-derived CAF cultures was unaffected. When tumor cells were cocultured with CAFs in a transwell system, the cetuximab-induced growth inhibition was reduced, and a complete protection from growth inhibition was observed in one of the tumor cell lines investigated. Media that had been conditioned by CAFs offered protection from cetuximab treatment in a concentration-dependent manner, suggesting that the resistance to treatment was mediated by CAF-derived soluble factors. The coculture of HNSCC cell lines with CAFs resulted in an elevated expression of matrix metalloproteinase-1 (MMP-1) in both the tumor cells and CAFs. Moreover, the CAF-induced resistance was partly abolished by the presence of an MMP inhibitor. However, CAFs treated with siRNA targeting MMP-1 still protected tumor cells from cetuximab treatment, suggesting that several MMPs may cooperate to facilitate resistance or that the protective effect is mediated by another member of the MMP family. These results identify a novel CAF-dependent modulation of cetuximab sensitivity and suggest that inhibiting MMPs may improve the effects of EGFR-targeted therapy. Mol Cancer Res; 10(9); 1158–68. ©2012 AACR.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Cancer-Associated Fibroblasts Induce Matrix Metalloproteinase–Mediated Cetuximab Resistance in Head and Neck Squamous Cell Carcinoma Cells

Johansson

Ansell

Jerhammar

et al. 2012

Molecular Cancer Research

103

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“…In comparison to NAF, CAF exhibit an increased production of type-specific collagens and a variety of growth factors and proteases (Tlsty 2001). As a consequence, CAF enhance tumor growth, facilitate metastasis, mediate resistance to chemotherapy and hormonal therapies, and promote neoangiogenesis (Horgan et al 1987;Noel et al 1993;Muerkoster et al 2004;Orimo et al 2005;Shekhar et al 2007;Ostman and Augsten 2009). The CAF phenotype is stimulated by paracrine signaling between cancer cells and resident fibroblasts or bone marrow-derived mesenchymal stem cells and is known to be induced by PDGF and Hedgehog ligand, both of which require PC for regulated signaling (Shao et al 2000;Ishii et al 2003;Kalluri and Zeisberg 2006;Zeisberg et al 2007;Bailey et al 2008;Ostman and Augsten 2009).…”

Section: Discussionmentioning

confidence: 99%

Primary Cilia Are Decreased in Breast Cancer: Analysis of a Collection of Human Breast Cancer Cell Lines and Tissues

Yuan

Frolova

Xie

et al. 2010

J Histochem Cytochem.

150

146

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S U M M A R Y Primary cilia (PC) are solitary, sensory organelles that are critical for several signaling pathways. PC were detected by immunofluorescence of cultured cells and breast tissues. After growth for 7 days in vitro, PC were detected in ?70% of breast fibroblasts and in 7-19% of epithelial cells derived from benign breast (184A1 and MCF10A). In 11 breast cancer cell lines, PC were present at a low frequency in four (from 0.3% to 4% of cells), but were absent in the remainder. The cancer cell lines with PC were all of the basal B subtype, which is analogous to the clinical triple-negative breast cancer subtype. Furthermore, the frequency of PC decreased with increasing degree of transformation/progression in the MCF10 and MDA-MB-435/LCC6 isogenic models of cancer progression. In histologically normal breast tissues, PC were frequent in fibroblasts and myoepithelial cells and less common in luminal epithelial cells. Of 26 breast cancers examined, rare PC were identified in cancer epithelial cells of only one cancer, which was of the triple-negative subtype. These data indicate a decrease or loss of PC in breast cancer and an association of PC with the basal B subtype. This manuscript contains online supplemental material at http://www.jhc.org. Please visit this article online to view these materials. (J Histochem Cytochem 58:857-870, 2010)

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“…Myofibroblasts form the source of many well-known tumorpromoting factors, including EGF, TGFβ or HGF. Previous studies have demonstrated that myofibroblasts affect sensitivity of malignant cells to chemo-or radiotherapy (17,18) and have a direct pro-metastatic effect (19).…”

Section: Discussionmentioning

confidence: 99%

Fusion between cancer cells and myofibroblasts is involved in osteosarcoma

Guo

Zhao

et al. 2011

Oncology Letters

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Abstract. Communication between cancer cells and the microenvironment appears to be an important determinant of disease prognosis. However, the detailed mechanisms of the interactions between cancer cells and surrounding cells have yet to be clarified. Recent studies on cell fusion have indicated this interaction to be one of the driving forces in cancer progression. Fibroblasts constitute a significant component of the carcinoma stromal compartment. Many of these fibroblasts are thought to differentiate into myofibroblasts, which are characterized by a positive expression of α-smooth muscle actin. Expression of α-smooth muscle actin in osteosarcoma was evaluated, and was observed to be excessive in the multinucleated osteoclast-like giant cells in osteosarcoma tissue, indicating the possibility of cell fusion between cancer cells and myofibroblasts. In order to test the above hypothesis, we first transformed the primary mouse embryonic fibroblast cells into activated myofibroblast cells. Osteosarcoma cells were then co-cultured with mouse myofibroblast cells, and cell fusion was investigated using species-specific chromosomal markers. Expression of α-smooth muscle actin was successfully induced in primary mouse embryonic fibroblast cells. Cells fused spontaneously with a fusion rate of approximately 1-2% and fusion between more than two cells was also observed. Our study demonstrated that fusion between cancer cells and myofibroblasts may contribute to the observed multinucleated giant cells in osteosarcoma. We posit that cell fusion is a novel mechanism for the interaction between cancer cells and the microenvironment.

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Direct Involvement of Breast Tumor Fibroblasts in the Modulation of Tamoxifen Sensitivity

Abstract: Using contact-dependent three-dimensional coculture systems and serum-free conditions, we compared the ability of estrogen receptor (ER)-␣

Cited by 92 publications

References 51 publications

Cancer-Associated Fibroblasts Induce Matrix Metalloproteinase–Mediated Cetuximab Resistance in Head and Neck Squamous Cell Carcinoma Cells

Cancer-Associated Fibroblasts Induce Matrix Metalloproteinase–Mediated Cetuximab Resistance in Head and Neck Squamous Cell Carcinoma Cells

Primary Cilia Are Decreased in Breast Cancer: Analysis of a Collection of Human Breast Cancer Cell Lines and Tissues

Fusion between cancer cells and myofibroblasts is involved in osteosarcoma

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