Dasatinib reverses Cancer-associated Fibroblasts (CAFs) from primary Lung Carcinomas to a Phenotype comparable to that of normal Fibroblasts

Haubeiss, Silke; Schmid, Jens O.; Mürdter, Thomas E.; Sonnenberg, Maike; Friedel, Godehard; Kuip, Heiko van der; Aulitzky, Walter E.

doi:10.1186/1476-4598-9-168

Cited by 69 publications

(44 citation statements)

References 26 publications

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“…Screening of a panel of small-molecule kinase inhibitors on CAF growth has identified five potent compounds, including three PDGFR inhibitors active at nanomolar concentrations. Testing of four FDA-approved PDGFR inhibitors (dasatinib, nilotinib, sorafenib, and imatinib) on 37 CAF strains identified dasatinib as the most effective compound (Haubeiss et al 2010). Tumor cells incubated with CM from CAFs preincubated with dasatinib exhibited reduced proliferation, confirming that dasatinib could blunt CAF tumor-promoting activity (Haubeiss et al 2010).…”

Section: Potential Therapies Aimed At Eliminating Cafsmentioning

confidence: 99%

“…Testing of four FDA-approved PDGFR inhibitors (dasatinib, nilotinib, sorafenib, and imatinib) on 37 CAF strains identified dasatinib as the most effective compound (Haubeiss et al 2010). Tumor cells incubated with CM from CAFs preincubated with dasatinib exhibited reduced proliferation, confirming that dasatinib could blunt CAF tumor-promoting activity (Haubeiss et al 2010). Promising results have also been obtained in a mouse model of cervical cancer (Jain et al 2008).…”

Section: Potential Therapies Aimed At Eliminating Cafsmentioning

confidence: 99%

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Carcinoma-associated fibroblasts: orchestrating the composition of malignancy

2016

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The tumor stroma is no longer seen solely as physical support for mutated epithelial cells but as an important modulator and even a driver of tumorigenicity. Within the tumor stromal milieu, heterogeneous populations of fibroblast-like cells, collectively termed carcinoma-associated fibroblasts (CAFs), are key players in the multicellular, stromal-dependent alterations that contribute to malignant initiation and progression. This review focuses on novel insights into the contributions of CAFs to disease progression, emergent events leading to the generation of CAFs, identification of CAF-specific biomarkers predictive of disease outcome, and recent therapeutic approaches aimed at blunting or reverting detrimental protumorigenic phenotypes associated with CAFs.

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Section: Potential Therapies Aimed At Eliminating Cafsmentioning

confidence: 99%

Section: Potential Therapies Aimed At Eliminating Cafsmentioning

confidence: 99%

Carcinoma-associated fibroblasts: orchestrating the composition of malignancy

2016

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“…Several studies have been carried out to target stromal fibroblasts using tyrosine kinase inhibitor, such as dasatinib or imatinib (Mueller et al, 2007a;Gioni et al, 2008;Haubeiss et al, 2010). Mueller et al (2007a) showed that imatinib inhibits proliferation and modulates cytokine expression of human cancerassociated fibroblasts from colorectal metastases.…”

Section: Discussionmentioning

confidence: 99%

Sunitinib mesylate inhibits proliferation of human colonic stromal fibroblasts in vitro and in vivo

Wang

Ruan

et al. 2014

J. Zhejiang Univ. Sci. B

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Abstract:Objective: Cancer stromal fibroblasts are important members of the cancer microenvironment. In this study, we determined the effect of sunitinib, a small molecule tyrosine kinase inhibitor, on the primary human colonic fibroblasts. Methods: Cell cycle analysis and cell proliferation assays were performed to evaluate the inhibitory effect of sunitinib in vitro. Western-blot analysis was performed to evaluate variations in the levels of phosphorylated plateletderived growth factor receptor β (PDGFR-β), Akt, and ERK proteins. Co-injection of SW620 cells and colonic fibroblasts in nude mice was employed to test anti-growth efficacy in vivo. Results: Sunitinib was found to effectively inhibit the growth of primary colonic fibroblasts. Low-dose sunitinib blocked the PDGF-BB-induced cell proliferation and PDGFR-β signaling. Co-injection of SW620 cells and colonic fibroblasts in nude mice generated greater tumor volumes than single injection of SW620 cells. Sunitinib treatment inhibited the SW620 cell+colonic fibroblast tumor growth more effectively than treatment of 5-fluorouracil. Conclusions: Sunitinib mesylate inhibited the proliferation of primary human colonic fibroblasts through target-inhibited PDGFR signaling in vitro and in vivo.

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“…Peripheral blood mononuclear cells (PBMC) and fibroblasts were isolated and maintained as described previously (13,14).…”

Section: Introductionmentioning

confidence: 99%

Cisplatin Hypersensitivity of Testicular Germ Cell Tumors Is Determined by High Constitutive Noxa Levels Mediated by Oct-4

et al. 2013

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Testicular germ cell tumors (TGCT) are considered a paradigm of chemosensitive tumors. Embryonal carcinoma cells represent the pluripotent entity of TGCTs and are characterized by expression of Oct-4, a key regulator of pluripotency and a determinant of their inherent hypersensitivity to cisplatin. However, the mechanisms underlying this Oct-4-mediated sensitivity are poorly understood. We previously showed that p53 is a major player in cisplatin hypersensitivity and therefore investigated whether Oct-4 may directly affect p53 activity. Despite a significant decrease in sensitivity, depletion of Oct-4 neither did alter cisplatin-induced transactivation of p53 target genes nor its subcellular localization. These data indicate that, rather than directly modulating p53 activity, Oct-4 provides a cellular context that augments the proapoptotic activity of p53. As mitochondrial priming by the Bcl-2 family is a known determinant of chemosensitivity, we compared the constitutive levels of these proteins in Oct-4-positive and -depleted cells. We identified Noxa as the only Bcl-2 family protein to be highly correlated with Oct-4 status and cisplatin sensitivity. Compared with differentiated cells, constitutive Noxa levels were significantly higher in Oct-4-positive cell lines and cancer patient samples. Furthermore, RNA interference-mediated knockdown of Oct-4 resulted in reduced Noxa transcript, in an almost complete loss of constitutive Noxa protein and decreased cisplatin hypersensitivity to a similar extent as did Noxa depletion. In conclusion, our study indicates that Noxa is a central determinant of hypersensitivity to cisplatin. Oct-4-dependent high constitutive levels of this BH3-only protein prime embryonal carcinoma cells to undergo rapid and massive apoptosis in response to p53 activation. Cancer Res; 73(5);

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Dasatinib reverses Cancer-associated Fibroblasts (CAFs) from primary Lung Carcinomas to a Phenotype comparable to that of normal Fibroblasts

Cited by 69 publications

References 26 publications

Carcinoma-associated fibroblasts: orchestrating the composition of malignancy

Carcinoma-associated fibroblasts: orchestrating the composition of malignancy

Sunitinib mesylate inhibits proliferation of human colonic stromal fibroblasts in vitro and in vivo

Cisplatin Hypersensitivity of Testicular Germ Cell Tumors Is Determined by High Constitutive Noxa Levels Mediated by Oct-4

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