Platelet-Derived Growth Factor-B Normalizes Micromorphology and Vessel Function in Vascular Endothelial Growth Factor-A-Induced Squamous Cell Carcinomas

Lederle, Wiltrud; Linde, Nina; Heusel, Julia; Bzyl, Jessica; Woenne, Eva C.; Zwick, Stefan; Skobe, Mihaela; Kießling, Fabian; Fusenig, Norbert E.; Mueller, Margareta M.

doi:10.2353/ajpath.2010.080998

Cited by 33 publications

(33 citation statements)

References 65 publications

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“…We also predict that tumors with larger amounts of VEGF grow in more compact shapes. Although the effects on tumor growth of overexpression of VEGF and its isoforms is incompletely understood, there is evidence that in some cases this overexpression may promote more compact tumor growth [38, 47]. …”

Section: Discussionmentioning

confidence: 99%

Multiscale Modeling of Glioblastoma Suggests that the Partial Disruption of Vessel/Cancer Stem Cell Crosstalk Can Promote Tumor Regression without Increasing Invasiveness

Yan

Romero-López

Frieboes

et al. 2016

IEEE Trans. Biomed. Eng.

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Objective In glioblastoma, the crosstalk between vascular endothelial cells (VECs) and glioma stem cells (GSCs) has been shown to enhance tumor growth. We propose a multiscale mathematical model to study this mechanism, explore tumor growth under various initial and microenvironmental conditions and investigate the effects of blocking this crosstalk. Methods We develop a hybrid continuum-discrete model of highly organized, vascularized tumors. VEC-GSC crosstalk is modeled via VEGF production by tumor cells and by secretion of soluble factors by VECs that promote GSC self-renewal and proliferation. Results VEC-GSC crosstalk increases both tumor size and GSC fraction by enhancing GSC activity and neovascular development. VEGF promotes vessel formation, and larger VEGF sources typically increase vessel numbers, which enhances tumor growth and stabilizes the tumor shape. Increasing the initial GSC fraction has a similar effect. Partially disrupting the crosstalk by blocking VEC secretion of GSC promoters reduces tumor size but does not increase invasiveness, which is in contrast to anti-angiogenic therapies, which reduce tumor size but may significantly increase tumor invasiveness. Significance Multiscale modeling supports the targeting of VEC-GSC crosstalk as a promising approach for cancer therapy.

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Section: Discussionmentioning

confidence: 99%

Multiscale Modeling of Glioblastoma Suggests that the Partial Disruption of Vessel/Cancer Stem Cell Crosstalk Can Promote Tumor Regression without Increasing Invasiveness

Yan

Romero-López

Frieboes

et al. 2016

IEEE Trans. Biomed. Eng.

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“…For EpoR staining, tissue sections were incubated with Epo-Cy5.5 (10 nM, 2 h at room temperature) before fixation. Fixation of the cryosections and the staining procedure were performed as previously described (26). Primary antibodies against CD31 (mCD31 rat; BD Biosciences), as well as corresponding secondary antibodies, were used as previously described (26)…”

Section: Imaging Protocolsmentioning

confidence: 99%

Targeted Near-Infrared Imaging of the Erythropoietin Receptor in Human Lung Cancer Xenografts

Doleschel¹,

Mundigl²,

Wessner³

et al. 2012

J Nucl Med

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“…OTCs were prepared as described . Briefly, dermal equivalents of native type I rat collagen (3.2 mg/ml), containing 2.5 × 10 5 normal human dermal fibroblasts, were poured into polycarbonate membrane filter inserts (Falcon no.…”

Section: Methodsmentioning

confidence: 99%

Cell type specific interleukin-6 induced responses in tumor keratinocytes and stromal fibroblasts are essential for invasive growth

et al. 2014

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Interleukin‐6 (IL‐6) is one of the major inflammatory interleukins that has been linked to cancer progression. In our model for human skin squamous cell carcinoma (SCC), IL‐6 expression is strongly upregulated upon progression from benign tumors to highly malignant, metastasizing SCCs. We now demonstrate that IL‐6 promotes malignant and invasive tumor growth in human skin SCCs by inducing cell type specific cytokine profiles in tumor keratinocytes and stromal fibroblasts, activating the latter towards a tumor associated fibroblast (TAF) phenotype. In three‐dimensional organotypic cocultures in vitro invasive growth of IL‐6 overexpressing tumor keratinocytes, is associated with increased expression of matrix metalloproteinase‐2 (MMP‐2), MMP‐14 and tissue inhibitor of metalloproteinases‐2, and clearly depends on IL‐6 activated fibroblasts. IL‐6‐induced secretion of monocyte chemotactic protein‐1 (MCP‐1) in tumor keratinocytes and of hepatocyte growth factor in fibroblasts is crucial for regulating expression and activation of MMP‐2. This functional role of IL‐6 is confirmed in vivo. Here MMP‐14 and MMP‐2 expression occur exclusively in surface transplants of IL‐6 overexpressing keratinocytes and fibroblasts are identified as important source of MMP‐2. Our data indicate that tumor keratinocytes derived IL‐6 activates stromal fibroblasts towards a TAF phenotype, promoting tumor invasion via enhanced expression and activation of MMP‐2.

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Platelet-Derived Growth Factor-B Normalizes Micromorphology and Vessel Function in Vascular Endothelial Growth Factor-A-Induced Squamous Cell Carcinomas

Abstract: Vascular endothelial growth factor (VEGF),

Cited by 33 publications

References 65 publications

Multiscale Modeling of Glioblastoma Suggests that the Partial Disruption of Vessel/Cancer Stem Cell Crosstalk Can Promote Tumor Regression without Increasing Invasiveness

Multiscale Modeling of Glioblastoma Suggests that the Partial Disruption of Vessel/Cancer Stem Cell Crosstalk Can Promote Tumor Regression without Increasing Invasiveness

Targeted Near-Infrared Imaging of the Erythropoietin Receptor in Human Lung Cancer Xenografts

Cell type specific interleukin-6 induced responses in tumor keratinocytes and stromal fibroblasts are essential for invasive growth

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