Abstract
Tumor barrier function in carcinoma represents a major challenge to treatment and is therefore an attractive target for increasing drug delivery. Variables related to tumor barrier include aberrant blood vessels, high interstitial fluid pressure, and the composition and structure of the extracellular matrix. One of the proteins associated with dense extracellular matrices is fibromodulin, a collagen fibrillogenesis modulator expressed in tumor stroma but scarce in normal loose connective tissues. Here, we investigated the effects of fibromodulin on stroma ECM in a syngeneic murine colon carcinoma model. We show that fibromodulin deficiency decreased collagen fibril thickness but glycosaminoglycan content and composition were unchanged. Furthermore, vascular density, pericyte coverage and macrophage amount were unaffected. Fibromodulin can therefore be a unique effector of dense collagen matrix assembly in tumor stroma and, without affecting other major matrix components or the cellular composition, can function as a main agent in tumor barrier function.
Highlights
Carcinoma stroma features a dense and dysfunctional extracellular matrix (ECM), which together with aberrant vessels and an underdeveloped lymphatic system, results in elevated interstitial fluid pressure (IFP) and barrier to treatment [1]
Gross morphological staining of OOC38 carcinoma grown in wild-type and in Fmod-/C57Bl6 mice did not reveal any noticeable difference in tumor appearance, i.e. in cancer cell distribution and density or in ECM localization (Fig 1A)
KAT-4 carcinoma grown in Fmod-/- SCID mice had a similar phenotype, manifested in increased extracellular volume (ECV), lowered IFP, and decreased collagen fibril thickness [22]. Based on these previous results we investigated whether fibromodulin deficiency decreased average collagen fibril thickness in syngeneic OOC38 carcinoma grown in Fmod-/- C57BL6 mice
Summary
Carcinoma stroma features a dense and dysfunctional extracellular matrix (ECM), which together with aberrant vessels and an underdeveloped lymphatic system, results in elevated interstitial fluid pressure (IFP) and barrier to treatment [1]. A dense stromal ECM can form a functional barrier for fluid transport, promote malignant progression, and impair blood flow [2,3,4,5]. These abnormalities negatively affect the outcome of chemo- and radio-therapeutic treatments [6,7,8,9]. Treatment with the tyrosine kinase inhibitor Imatinib (STI-571) reduces IFP, increases extracellular volume (ECV), and increases tumor perfusability, as evidenced by increased fluid transport and tumor tissue oxygenation in ECM-rich
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