Increased Fibrosis and Interstitial Fluid Pressure in Two Different Types of Syngeneic Murine Carcinoma Grown in Integrin β3-Subunit Deficient Mice

Friman, Tomas; Gustafsson, Ronny; Stuhr, Linda Elin Birkhaug; Heldin, Nils‐Erik; Reed, Rolf K.; Oldberg, Åke; Rubin, Kristofer

doi:10.1371/journal.pone.0034082

Cited by 14 publications

(17 citation statements)

References 41 publications

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“…Previous studies have revealed a correlation between IFP and the properties of the collagen network in stroma such as collagen fibril density, fibril structure, or network architecture in experimental carcinomas (7)(8)(9)(10)(11). In normal loose connective tissues, IFP is actively controlled by connective tissue cells that exert a tension on the collagen/microfibrillar network, thereby restraining the swelling of the underhydrated glycosaminoglycan (GAG)/proteoglycan ground substance (12).…”

Section: Introductionmentioning

confidence: 99%

The Tyrosine Kinase Inhibitor Imatinib Augments Extracellular Fluid Exchange and Reduces Average Collagen Fibril Diameter in Experimental Carcinoma

Olsson

Gustafsson

Zandt

et al. 2016

Molecular Cancer Therapeutics

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A typical obstacle to cancer therapy is the limited distribution of low molecular weight anticancer drugs within the carcinoma tissue. In experimental carcinoma, imatinib (STI571) increases efficacy of synchronized chemotherapy, reduces tumor interstitial fluid pressure, and increases interstitial fluid volume. STI571 also increases the water-perfusable fraction in metastases from human colorectal adenocarcinomas. Because the mechanism(s) behind these effects have not been fully elucidated, we investigated the hypothesis that STI571 alters specific properties of the stromal extracellular matrix. We analyzed STI571-treated human colorectal KAT-4/HT-29 experimental carcinomas, known to have a welldeveloped stromal compartment, for solute exchange and glycosaminoglycan content, as well as collagen content, structure, and synthesis. MRI of STI571-treated KAT-4/HT-29 experimental carcinomas showed a significantly increased efficacy in dynamic exchanges of solutes between tumor interstitium and blood. This effect was paralleled by a distinct change of the stromal collagen network architecture, manifested by a decreased average collagen fibril diameter, and increased collagen turnover. The glycosaminoglycan content was unchanged. Furthermore, the apparent effects on the stromal cellular composition were limited to a reduction in an NG2-positive stromal cell population. The current data support the hypothesis that the collagen network architecture influences the dynamic exchanges of solutes between blood and carcinoma tissue. It is conceivable that STI571 reprograms distinct nonvascular stromal cells to produce a looser extracellular matrix, ultimately improving transport characteristics for traditional chemotherapeutic agents. Mol Cancer Ther; 15(10); 2455-64. Ó2016 AACR.

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Section: Introductionmentioning

confidence: 99%

The Tyrosine Kinase Inhibitor Imatinib Augments Extracellular Fluid Exchange and Reduces Average Collagen Fibril Diameter in Experimental Carcinoma

Olsson

Gustafsson

Zandt

et al. 2016

Molecular Cancer Therapeutics

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“…Since it has been suggested earlier that collagen structure could influence PIF [ 32 , 33 ], we also decided to evaluate collagen structure in this study. The collagen fibril diameter from Transmission Electron Microscope (TEM) analyses of 4T1 tumors revealed an uneven distribution in fibril diameter leading to a clear shift towards thicker collagen fibrils in carcinomas grown in β3-KO mice compared to WT mice ( Figure 7 A).…”

Section: Resultsmentioning

confidence: 99%

The Effect of Stromal Integrin β3-Deficiency on Two Different Tumors in Mice

Reigstad

Sortland

Skogstrand

et al. 2016

Cancers

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There is an increasing focus on the tumor microenvironment in carcinogenesis. Integrins are important receptors and adhesion molecules in this environment and have been shown to be involved in cell adhesion, proliferation, differentiation and migration. The present study aimed to evaluate the effect of stromal integrin β3-deficiency on tumor growth, angiogenesis, interstitial fluid pressure (PIF), fibrosis and metastasis in a murine breast cancer (4T1) and a prostate tumor (RM11) model. We showed that stromal integrin β3-deficiency led to an elevation in PIF that correlated to a shift towards thicker collagen fibrils in the 4T1 mammary tumor. In the RM11 prostate carcinoma model there was no effect of integrin β3-deficiency on PIF and collagen fibril thickness. These findings support the notion that changes in the collagen scaffold influence PIF, and also indicate that there must be important crosstalk between the stroma and tumor cells, in a tumor cell line specific manner. Furthermore, stromal integrin β3-deficiency had no effect on tumor growth or angiogenesis in both tumor models and no effect on lung metastasis in the 4T1 mammary tumor model. In conclusion, the stromal β3 integrin influence PIF, possibly via its effect on the structure of the collagen network, in a tumor cell line dependent manner.

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“…An increased amount of hyaluronan in TME causes an increase in matrix expansion. It also has the ability to promote the survival of metastatic cancer cells (10).…”

Section: Solid Pressurementioning

confidence: 99%

Releasing Pressure in Tumors: What Do We Know So Far and Where Do We Go from Here? A Review

et al. 2014

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Tumor interstitial pressure is a fundamental feature of cancer biology. Elevation in tumor pressure affects the efficacy of cancer treatment. It causes heterogenous intratumoral distribution of drugs and macromolecules. It also causes the development of hypoxia within tumor bulk, leading to reduced efficacy of therapeutic drugs and radiotherapy. Tumor pressure has been associated with increased metastatic potential and poor prognosis in some tumors. The formation of increased pressure in solid tumors is multifactorial. Factors known to affect tumor pressure include hyperpermeable tortuous tumor vasculatures, the lack of functional intratumoral lymphatic vessels, abnormal tumor microenvironment, and the solid stress exerted by proliferating tumor cells. Reducing this pressure is known to enhance the uptake and homogenous distribution of many therapies. Pharmacologic and biologic agents have been shown to reduce tumor pressure. These include antiangiogenic therapy, vasodilatory agents, antilymphogenic therapy, and proteolytic enzymes. Physical manipulation has been shown to cause reduction in tumor pressure. These include irradiation, hyperbaric oxygen therapy, hyper-or hypothermic therapy, and photodynamic therapy. This review explores the methods to reduce tumor pressure that may open up new avenues in cancer treatment. Cancer Res; 74(10); 2655-62. Ó2014 AACR.

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Increased Fibrosis and Interstitial Fluid Pressure in Two Different Types of Syngeneic Murine Carcinoma Grown in Integrin β3-Subunit Deficient Mice

Cited by 14 publications

References 41 publications

The Tyrosine Kinase Inhibitor Imatinib Augments Extracellular Fluid Exchange and Reduces Average Collagen Fibril Diameter in Experimental Carcinoma

The Tyrosine Kinase Inhibitor Imatinib Augments Extracellular Fluid Exchange and Reduces Average Collagen Fibril Diameter in Experimental Carcinoma

The Effect of Stromal Integrin β3-Deficiency on Two Different Tumors in Mice

Releasing Pressure in Tumors: What Do We Know So Far and Where Do We Go from Here? A Review

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