Interference with TGF‐β1 and ‐β3 in tumor stroma lowers tumor interstitial fluid pressure independently of growth in experimental carcinoma

Lammerts, Ellen; Roswall, Pernilla; Sundberg, Christian; Gotwals, Philip J.; Koteliansky, Victor; Reed, Rolf K.; Heldin, Nils‐Erik; Rubin, Kristofer

doi:10.1002/ijc.10722

Cited by 52 publications

(45 citation statements)

References 40 publications

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“…19 Tumor IFP was measured by the 'wick-in-the needle' technique as described. 5 All animal experiments were approved by the Ethical Committee for Animal Experiments in Uppsala (Sweden).…”

Section: Tumors and Treatmentsmentioning

confidence: 99%

“…19 The pellet (25 000 g) of insoluble cellular components from the lysis was subjected to sonication in 50 mM Tris HCl pH 7.4, 5 mM EDTA and 1% sodium dodecylsulfate. Immunoblot analyses were performed as previously described, 19 on both cell fractions using the anti-NG2 or anti-aSMA antibodies. The second solubilization appeared to contain approximately 70-80% of the specific signal in the NG2 immunoblots.…”

Section: Immunoblot Analysismentioning

confidence: 99%

“…19 Expression of mouse (host) genes was investigated by mouse Affymetrix microarray analyses. Differences in gene expressions in carcinomas from animals treated with Fc:TbRII (n ¼ 3) or IgG 2A (n ¼ 3) were compared.…”

Section: Fc:tbrii Downregulates Genes Expressed By Macrophagesmentioning

confidence: 99%

“…17,18 Treatment of xenograft human KAT-4 anaplastic thyroid carcinoma in mice with a soluble TGF-b receptor type IImurine Fc:IgG 2A chimeric protein (Fc:TbRII) lowered tumor IFP in a dose-and time-dependent manner. 19 The present study was initiated to delineate potential mechanisms by which Fc:TbRII reduced KAT-4 carcinoma IFP. KAT-4 carcinomas were chosen since they are well characterized and cultured KAT-4 carcinoma cells are refractory to TGF-b.…”

mentioning

confidence: 99%

“…KAT-4 carcinomas were chosen since they are well characterized and cultured KAT-4 carcinoma cells are refractory to TGF-b. 19 …”

mentioning

confidence: 99%

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Inhibition of TGF-β modulates macrophages and vessel maturation in parallel to a lowering of interstitial fluid pressure in experimental carcinoma

Salnikov

Roswall²,

Sundberg

et al. 2005

Laboratory Investigation

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A pathologically elevated interstitial fluid pressure (IFP) is a characteristic of both clinical and experimental carcinoma. The soluble TGF-b receptor type II-murine Fc:IgG 2A chimeric protein (Fc:TbRII) lowers IFP in the KAT-4 experimental model for anaplastic thyroid carcinoma. Analyses of messenger RNA (mRNA) expressions by Affymetrix microarrays and RNase protection assays, as well as of protein expressions identified tumor macrophages as targets for Fc:TbRII. Treatment with Fc:TbRII reduced albumin extravasation, increased coverage of a-smooth muscle actin-positive cells and reduced expression of NG2, a marker of activated pericytes, in KAT-4 carcinoma blood vessels. Specific inhibition of interleukin-1 (IL-1), a major cytokine produced by activated macrophages, lowered carcinoma IFP to a similar degree as Fc:TbRII but had no significant effect on the parameters of blood vessel maturation. Neither Fc:TbRII nor inhibition of IL-1 changed blood vessel density. Finally, pretreatment of KAT-4 carcinomas with Fc:TbRII increased the antitumor efficacy of doxorubicin. Our data emphasize a potential role of tumor macrophages in carcinoma physiology and identify these cells as potential stromal targets for treatment aimed to improve efficacy of chemotherapy.

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“…19 Tumor IFP was measured by the 'wick-in-the needle' technique as described. 5 All animal experiments were approved by the Ethical Committee for Animal Experiments in Uppsala (Sweden).…”

Section: Tumors and Treatmentsmentioning

confidence: 99%

Section: Immunoblot Analysismentioning

confidence: 99%

Section: Fc:tbrii Downregulates Genes Expressed By Macrophagesmentioning

confidence: 99%

mentioning

confidence: 99%

“…KAT-4 carcinomas were chosen since they are well characterized and cultured KAT-4 carcinoma cells are refractory to TGF-b. 19 …”

mentioning

confidence: 99%

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Inhibition of TGF-β modulates macrophages and vessel maturation in parallel to a lowering of interstitial fluid pressure in experimental carcinoma

Salnikov

Roswall²,

Sundberg

et al. 2005

Laboratory Investigation

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Improving delivery of antineoplastic agents with anti‐vascular endothelial growth factor therapy

Yang

Bauer

Camp

et al. 2005

Cancer

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Inhibition of carcinoma cell‐derived VEGF reduces inflammatory characteristics in xenograft carcinoma

Salnikov

Heldin

Stuhr

et al. 2006

Intl Journal of Cancer

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The stroma of carcinomas shares several characteristics with inflamed tissues including a distorted vasculature, active angiogenesis and macrophage infiltration. In addition, the tumor interstitial fluid pressure (P IF ) of the stroma is pathologically elevated. We show here that bevacizumab [rhuMab vascular endothelial growth factor (VEGF), Avastin], a monoclonal antibody to VEGF, at a dose of 5 mg/kg modulated inflammation in KAT-4 xenograft human anaplastic thyroid carcinoma tissue. At this dose, bevacizumab reduced the density of macrophages, MHC class II antigen expression by macrophages and IL-1b mRNA expression. Furthermore, bevacizumab lowered tumor extracellular fluid volume, plasma protein leakage from tumor vessels, the number of CD31-positive structures and tumor P IF . The tumor plasma volume and the number of a-smooth muscle actin-positive vessels, however, remained unchanged. Our data suggest that carcinoma cellderived VEGF either directly or indirectly participates in maintaining an inflammatory microenvironment in experimental KAT-4 carcinoma. Furthermore, our data indicate that the reduction of inflammation resulting in reduced vascular permeability and decrease in the tumor extracellular fluid volume by bevacizumab contributes to reduced tumor P IF .

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Interference with TGF‐β1 and ‐β3 in tumor stroma lowers tumor interstitial fluid pressure independently of growth in experimental carcinoma

Cited by 52 publications

References 40 publications

Inhibition of TGF-β modulates macrophages and vessel maturation in parallel to a lowering of interstitial fluid pressure in experimental carcinoma

Inhibition of TGF-β modulates macrophages and vessel maturation in parallel to a lowering of interstitial fluid pressure in experimental carcinoma

Improving delivery of antineoplastic agents with anti‐vascular endothelial growth factor therapy

Inhibition of carcinoma cell‐derived VEGF reduces inflammatory characteristics in xenograft carcinoma

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