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Collagen-Binding Proteoglycan Fibromodulin Can Determine Stroma Matrix Structure and Fluid Balance in Experimental Carcinoma

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Collagen-Binding Proteoglycan Fibromodulin Can Determine Stroma Matrix Structure and Fluid Balance in Experimental Carcinoma Collagen-binding proteoglycan fibromodulin can determine stroma matrix structure and fluid balance in experimental carcinoma Åke Oldberg*, Sebastian Kalamajski*, Alexei V. Salnikov†‡§, Linda Stuhr¶, Matthias Mo¨ rgelinʈ, Rolf K. Reed¶, Nils-Erik Heldin**, and Kristofer Rubin†,†† *Department of Experimental Medical Sciences, BMC, B-12, and ʈDepartment of Clinical Sciences, BMC B14, University of Lund, SE-221 84 Lund, Sweden; †Department of Medical Biochemistry and Microbiology, Uppsala University, BMC, Box 582, SE-751 23 Uppsala, Sweden; ‡Oncology Clinic, University Hospital Lund, SE-221 85 Lund, Sweden; ¶Department of Biomedicine, University of Bergen, N-5009 Bergen, Norway and **Department of Genetics and Pathology, Uppsala University Hospital, Rudbeck Laboratory, SE-751 85 Uppsala, Sweden Edited by Erkki Ruoslahti, Burnham Institute for Medical Research, Santa Barbara, CA, and approved July 16, 2007 (received for review March 7, 2007) Research on the biology of the tumor stroma has the potential to Clara, CA) of Fc:T␤RII-treated KAT-4 carcinomas revealed lead to development of more effective treatment regimes enhanc- down-regulations predominantly of macrophage-related genes ing the efficacy of drug-based treatment of solid malignancies. (17). Furthermore, inhibition of IL-1 reduces IFP in these Tumor stroma is characterized by distorted blood vessels and carcinomas (17). These findings indicate a role of inflammation activated connective tissue cells producing a collagen-rich matrix, in the generation of an elevated IFP. Tortuous and leaky blood which is accompanied by elevated interstitial fluid pressure (IFP), vessels, and absence of lymph drainage in tumors have also been indicating a transport barrier between tumor tissue and blood. suggested to be involved in the generation of the elevated tumor Here, we show that the collagen-binding proteoglycan fibromodu- IFP. Inhibition of plasma protein leakage by interfering with lin controls stroma structure and fluid balance in experimental vascular endothelial growth factor reduces IFP in experimental carcinoma. Gene ablation or inhibition of expression by anti- carcinomas (18, 19) and human rectal carcinoma (15). Little is inflammatory agents showed that fibromodulin promoted the known, however, about how the structure and composition of the formation of a dense stroma and an elevated IFP. Fibromodulin- ECM in the stroma influence carcinoma IFP. deficiency did not affect vasculature but increased the extracellular The small leucine-rich repeat proteoglycan fibromodulin has fluid volume and lowered IFP. Our data suggest that fibromodulin a known role in collagen assembly and maintenance (20). controls stroma matrix structure that in turn modulates fluid Fibromodulin is expressed in dense regular connective tissues, convection inside and out of the stroma. This finding is particularly such as tendons, ligaments, and cartilage, but is absent or important in relation to the demonstration that targeted modula- expressed at low levels in skin, bone, and visceral organs (21, 22). tions of the fluid balance in carcinoma can increase the response to Fibromodulin controls collagen matrix structure in tendons and cancer therapeutic agents. ligaments, and deficient mice show altered tissue organization with fewer and structurally abnormal collagen fiber bundles. The physiology ͉ TGF-␤ ͉ tumor physiology ͉ inflammation ͉ collagen fibrils are thinner (23), tendons and ligaments have interstitial fluid pressure reduced tensile strength, and the animals develop knee-joint instability and osteoarthritis (24–26). Fibromodulin mRNA has espite advances in our knowledge of causative factors and been detected in a variety of clinical malignancies, such as lung, Dgenetic changes during development of the malignant ge- breast, and prostate carcinomas (27–29). Here, we report that notype, treatment results and mean survival time for patients fibromodulin has a role in regulating stroma ECM structure and suffering from advanced cancer have improved only marginally. fluid balance in carcinoma. In recent years, partly in response to disillusion with the available Results cytotoxic cancer chemotherapeutic agents, attention has turned to the stromal elements of tumors. Abnormal blood vessels and We were led to fibromodulin by the finding that in addition to ␤ connective tissue cells that produce a fibrotic collagen-rich lower expression of macrophage-related genes, Fc:T RII sig- matrix characterize the stroma of a carcinoma (1–4). Invasive- nificantly down-regulated mRNA encoding fibromodulin. No- ness and growth of malignant cells are affected by interactions tably, mRNA levels encoding other ECM proteins, such as with the stroma (5), and in this respect a carcinoma resembles an collagen type I, fibronectin, and decorin were unchanged [sup- inflammatory lesion (6) or a wound that will not heal (7). A porting information (SI) Table 3]. Initially, we determined that mathematical model of cancer invasion recently suggested that fibromodulin showed a wide-ranging expression in experimental a heterogeneous extracellular matrix (ECM) with varying ECM carcinomas, such as chemically induced rat mammary carci- component densities selects aggressive tumor cell phenotypes, whereas tumors with a homogenous ECM are less aggressive and Author contributions: Å.O., S.K., and K.R. designed research; Å.O., S.K., A.V.S., L.S., R.K.R., invasive (8). N.-E.H., and K.R. performed research; Å.O., S.K., A.V.S., L.S., M.M., R.K.R., N.-E.H., and K.R. Carcinomas have a pathologically elevated interstitial fluid analyzed data; Å.O., R.K.R., and K.R. wrote the paper. pressure (IFP) indicating a transport barrier between tumor The authors declare no conflict of interest. tissue and blood (9–11). Indeed, pharmaceutical treatments that This article is a PNAS Direct Submission. lower IFP in experimental carcinoma (12–14) and human can- Abbreviations: ECM, extracellular matrix; EBD, Evans’ blue dye; IFP, interstitial fluid pres- cers (ref 15 and references therein) also increase efficacy of sure; ECV, extracellular fluid volumes. cytostatic treatment. Treatment of mice carrying a xenografted §Present address: Division of Molecular Immunology, German Cancer Research Center, human anaplastic thyroid carcinoma (KAT-4) with the soluble D-69120 Heidelberg, Germany. TGF-␤ receptor type II-murine Fc:IgG2A chimeric protein ††To whom correspondence should be addressed. E-mail: [email protected]. (Fc:T␤RII), which inhibits TGF-␤1 and -␤3, lowers IFP, reduces This article contains supporting information online at www.pnas.org/cgi/content/full/ plasma protein leakage, and enhances the anti-tumor effect of 0702014104/DC1. doxorubicin (16, 17). Microarray analyses (Affymetrix, Santa © 2007 by The National Academy of Sciences of the USA 13966–13971 ͉ PNAS ͉ August 28, 2007 ͉ vol. 104 ͉ no. 35 www.pnas.org͞cgi͞doi͞10.1073͞pnas.0702014104 Downloaded by guest on October 1, 2021 A B C D EF G H Fig. 1. Expression of fibromodulin in carcinomas. (A–C) Immunoperoxidase staining of fibromodulin in PROb rat colonic carcinoma (A), DMBA-induced rat breast carcinoma (B), and mouse RIP-Tag insulinomas (C). Quantitative real- time PCR of KAT-4 tumors from mice treated with control IgG2A or Fc:T␤RII. (D) The difference in mRNA levels between treated and untreated tumors was significant (P Ͻ 0.05, n ϭ 3). (E and F) Staining of fibromodulin in control IgG2A-treated (E) and Fc:T␤RII-treated (F) mice carrying KAT-4 carcinomas. (G and H) Fibromodulin stainings of KAT-4 carcinoma xenografted in WT (G) and Fig. 2. Tumor stroma ultrastructure. (A–D) Transmission electron micro- Fmod-null (H) mice. Mice carrying KAT-4 carcinoma were treated with vehicle graphs of KAT-4 carcinomas grown in WT (A), fibromodulin-deficient (B), or Fc:T␤RII (10 mg/kg) 10 days before killing (16). Tumors were frozen, sec- control IgG2A-treated (C), and Fc:T␤RII-treated (D) mice. (Magnification, A–D, tioned, stained with a rabbit anti-bovine fibromodulin antiserum, and coun- ϫ25,000; scale bar, 200 nm.) (E) Morphometric analyses of collagen fibrils in terstained with hematoxylin (23). (Scale bar, 100 ␮m.) carcinomas grown in WT (open bars) and fibromodulin-deficient (filled bars) mice. (F) Collagen fibril diameters in control IgG2A-treated (open bars) and ␤ Fc:T RII-treated (filled bars) carcinomas. (G and H) Scanning electron micro- CELL BIOLOGY noma, mouse RIP-Tag insulinoma, transplantable syngeneic graphs of carcinomas grown in WT (G) and Fmod-null (H) mice. (I and J) Control ␤ ϫ colonic carcinoma (PROb), and KAT-4 carcinoma growing as a IgG2A-treated (I) and Fc:T RII-treated (J) mice (Magnification, G–J 300; scale xenograft in nude mice (Fig. 1). Staining was restricted to the bar, 100 ␮m). Quantification by image analyses of entire whole-mount tumors revealed that the collagen scaffold density was significantly higher (P Ͻ 0.008) stroma compartment in the carcinomas. This finding is consis- Ϯ ϭ tent with the absence of fibromodulin in normal murine skin, in WT (60 4 pixels per area unit, n 4) (G) compared with Fmod-null carcinomas (45 Ϯ 0.5 pixels per area unit, n ϭ 4) (H). Collagen densities in thyroid, and colon (SI Fig. 5 A–C), which is in agreement with control carcinomas (IgG2A-treated) were 62 Ϯ 4 pixels per unit area (n ϭ 3) (I) the reported distribution of fibromodulin (21, 22). Cultured compared with 49 Ϯ 3 pixels per unit area (n ϭ 3) in Fc:T␤RII-treated carcino- KAT-4 and PROb cells did not express fibromodulin mRNA or mas (J)(P Ͻ 0.03). protein (data not shown). Quantitative PCR analyses showed that treatment of KAT-4 carcinomas with Fc:T␤RII reduced Ϸ fibromodulin mRNA by 50% (Fig. 1D). Immunohistochemical Stroma collagen fibrils in WT and heterozygous mice were analyses showed that fibromodulin protein expression was also similar with an average diameter of 43 nm, whereas those in reduced (Figs. 1 E–F). No staining was seen in carcinomas from KAT-4 carcinomas grown in Fmod-null mice were significantly Fmod-null mice (Fig. 1H).
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