Interstitial fluid pressure, vascularity and metastasis in ectopic, orthotopic and spontaneous tumours

Sarah Jane Lunt,Victor X Yang,Michael Milosevic,Richard P Hill,Tuula Mk Kalliomaki,Allison Brown

doi:10.1186/1471-2407-8-2

Abstract

BackgroundHigh tumour interstitial fluid pressure (IFP) has been adversely linked to poor drug uptake in patients, and to treatment response following radiotherapy in cervix cancer patients. In this study we measured IFP values in a selection of murine and xenograft models, spontaneously arising or transplanted either intramuscularly (i/m) or orthotopically and analysed their relationship to tumour vascularity and metastatic spread.MethodsKHT-C murine fibrosarcoma, ME180 and SiHa human cervix carcinoma were grown either intramuscularly (i/m), sub-cutaneously (s/c) or orthotopically. Polyoma middle-T (MMTV-PyMT) transgenic spontaneous mammary tumours were studied either as spontaneous tumours or following orthotopic or i/m transplantation. IFP was measured in all tumours using the wick-in-needle method. Spontaneous metastasis formation in the lungs or lymph nodes was assessed in all models. An immunohistochemical analysis of tumour hypoxia, vascular density, lymphatic vascular density and proliferation was carried out in ME180 tumours grown both i/m and orthotopically. Blood flow was also assessed in the ME180 model using high-frequency micro-ultrasound functional imaging.ResultsTumour IFP was heterogeneous in all the models irrespective of growth site: KHT-C i/m: 2–42 mmHg, s/c: 1–14 mmHg, ME180: i/m 5–68 mmHg, cervix 4–21 mmHg, SiHa: i/m 20–56 mmHg, cervix 2–26 mmHg, MMTV-PyMT: i/m: 13–45 mmHg, spontaneous 2–20 mmHg and transplanted 2–22 mmHg. Additionally, there was significant variation between individual tumours growing in the same mouse, and there was no correlation between donor and recipient tumour IFP values. Metastatic dissemination to the lungs or lymph nodes demonstrated no correlation with tumour IFP. Tumour hypoxia, proliferation, and lymphatic or blood vessel density also showed no relationship with tumour IFP. Speckle variance analysis of ultrasound images showed no differences in vascular perfusion between ME180 tumours grown i/m versus orthotopically despite differences in IFP.ConclusionOur studies across a range of different tumour models showed substantial heterogeneity in tumour IFP, suggesting differences in the vascular development and interstitial fluid dynamics in the individual tumours. The results demonstrate a strong stochastic aspect to tumour IFP development, notably the variation apparent between different tumours within the same animal and the lack of correlation between donor and recipient tumours.

Highlights

High tumour interstitial fluid pressure (IFP) has been adversely linked to poor drug uptake in patients, and to treatment response following radiotherapy in cervix cancer patients
Tumour IFP was measured in a number of different murine and xenograft tumour models grown both ectopically and orthotopically
Our findings indicate systematic differences in IFP as a function of tumour type consistent with predetermined inherent genetic differences that influence vascular development and the composition and organisation of the interstitium

Summary

Introduction

High tumour interstitial fluid pressure (IFP) has been adversely linked to poor drug uptake in patients, and to treatment response following radiotherapy in cervix cancer patients. Tumour angiogenesis generates abnormal vessels [1,2,3] that demonstrate several anomalies including an incomplete or absent endothelial cell layer and basement membrane which makes them hyper-permeable [4] These vessels exhibit a high resistance to capillary blood flow and a low resistance to transcapillary flow, resulting in a net efflux of fluid into the surrounding interstitial space where a lack of functional lymphatics allows it to accumulate, distending the elastic extracellular matrix and increasing the interstitial pressure [5,6]. The tumour interstitium itself is thought to be abnormal, comprising a dense network of collagen fibres, as well as increased fibroblasts, macrophages and other cells involved in inflammation, which further contribute to elevated IFP values [3]. The pathophysiologic mechanisms underlying widely varying IFP values in human and experimental tumours of the same and differing types, and the influence of growth site and the host, is less well understood

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