Mechanical induction of the tumorigenic ß-catenin pathway by tumour growth pressure.

The tumour microenvironment may contribute to tumorigenesis owing to mechanical forces such as fibrotic stiffness or mechanical pressure caused by the expansion of hyper-proliferative cells. Here we explore the contribution of the mechanical pressure exerted by tumour growth onto non-tumorous adjacent epithelium. In the early stage of mouse colon tumour development in the Notch(+)Apc(+/1638N) mouse model, we observed mechanistic pressure stress in the non-tumorous epithelial cells caused by hyper-proliferative adjacent crypts overexpressing active Notch, which is associated with increased Ret and ß-catenin signalling. We thus developed a method that allows the delivery of a defined mechanical pressure in vivo, by subcutaneously inserting a magnet close to the mouse colon. The implanted magnet generated a magnetic force on ultra-magnetic liposomes, stabilized in the mesenchymal cells of the connective tissue surrounding colonic crypts after intravenous injection. The magnetically induced pressure quantitatively mimicked the endogenous early tumour growth stress in the order of 1,200 Pa, without affecting tissue stiffness, as monitored by ultrasound strain imaging and shear wave elastography. The exertion of pressure mimicking that of tumour growth led to rapid Ret activation and downstream phosphorylation of ß-catenin on Tyr654, imparing its interaction with the E-cadherin in adherens junctions, and which was followed by ß-catenin nuclear translocation after 15 days. As a consequence, increased expression of ß-catenin-target genes was observed at 1 month, together with crypt enlargement accompanying the formation of early tumorous aberrant crypt foci. Mechanical activation of the tumorigenic ß-catenin pathway suggests unexplored modes of tumour propagation based on mechanical signalling pathways in healthy epithelial cells surrounding the tumour, which may contribute to tumour heterogeneity.

Feasibility of Imaging and Treatment Monitoring of Breast Lesions with Three-Dimensional Shear Wave Elastography.

Purpose Firstly to evaluate the feasibility and diagnostic performance of three-dimensional (3 D) shear wave elastography (SWE) volume measurements in patients with breast lesions compared to breast dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) lesion volumes and 3D-US B-mode volumes. Secondly to assess the treatment monitoring performance of 3D-SWE in patients under neoadjuvant chemotherapy for breast cancer by comparing it to 3D-US lesion volume. Materials and Methods This prospective study was approved by the institutional review board. Informed consent was provided. 33 patients with 33 lesions were included. The feasibility of 3D-SWE was evaluated in 23 patients. In the 10 remaining patients receiving neoadjuvant chemotherapy, 3D-SWE was evaluated before and during treatment. Tumor volume and qualitative and quantitative elasticity analysis measurements were performed and compared to the tumor volume as estimated by 3D-US and DCE-MRI. Statistical analysis was performed using the Pearson correlation coefficient. Results 3D-SWE was feasible in patients with breast lesions. Tumor volume calculated with 3D-US and 3D-SWE showed very good and moderate concordances with DCE-MRI volume, respectively (Pearson correlation coefficients equal to ρ = r = 0.88, p < 0.00 002 and ρ = r = 0.5, p = 0.32, respectively). Modification of tumor elasticity and heterogeneity was correlated with response to treatment. In good responders, elasticity and elasticity heterogeneity diminished. Conclusion Tumor 3D-US volume measurements showed very good concordance with DCE-MRI volume. 3D-SWE can provide valuable information: reduction of tissue stiffness during treatment could be a potential indicator of response. These preliminary results should be confirmed on a larger number of patients.

Evaluation of Antivascular Combretastatin A4 P Efficacy Using Supersonic Shear Imaging Technique of Ectopic Colon Carcinoma CT26.

A recent ultrasound imaging technique-shear wave elastography-showed its ability to image and quantify the mechanical properties of biological tissues, such as prostate or liver tissues. In the present study this technique was used to evaluate the relationship among tumor growth, stiffness and reduction of treatment with combretastatin (CA4 P) in allografted colon tumor CT26 in mice. During 12 d, CT26 tumor growth (n = 52) was imaged by ultrasound, and shear modulus was quantified, showing a good correlation between tumor volume and stiffness (r = 0.59). The treatment was initiated at d 12 and monitored every d during 4 d. Following the treatment, the tumor volume had decreased, while the elasticity of the tumor volume remained steady throughout the treatment. After segmentation using the shear modulus map, a detailed analysis showed a decrease in the stiffness after treatment. This reduction in the mechanical properties was shown to correlate with tissue reorganization, particularly, fibrosis and necrosis, assessed by histology.

Supersonic Shear Wave Elastography of Response to Anti-cancer Therapy in a Xenograft Tumor Model.

Our objective was to determine if supersonic shear wave elastography (SSWE) can detect changes in stiffness of a breast cancer model under therapy. A human invasive carcinoma was implanted in 22 mice. Eleven were treated with an anti-angiogenic therapy and 11 with glucose for 24 d. Tumor volume and stiffness were assessed during 2 wk before treatment and 0, 7, 12, 20 and 24 d after the start of therapy using SSWE. Pathology was assessed after 12 and 24 d of treatment. We found that response to therapy was associated with early softening of treated tumors only, resulting in a significant difference from non-treated tumors after 12 d of treatment (p = 0.03). On pathology, large areas of necrosis were observed at 12 d in treated tumors. Although treatment was still effective, treated tumors subsequently stiffened during a second phase of the treatment (days 12-24), with a small amount of necrosis observed on pathology on day 24. In conclusion, SSWE was able to measure changes in the stiffness of tumors in response to anti-cancer treatment. However, stiffness changes associated with good response to treatment may change over time, and increased stiffness may also reflect therapy efficacy.

Evaluation of Nonradiative Clinical Imaging Techniques for the Longitudinal Assessment of Tumour Growth in Murine CT26 Colon Carcinoma.

Background and Objectives. To determine the most appropriate technique for tumour followup in experimental therapeutics, we compared ultrasound (US) and magnetic resonance imaging (MRI) to characterize ectopic and orthotopic colon carcinoma models. Methods. CT26 tumours were implanted subcutaneously (s.c.) in Balb/c mice for the ectopic model or into the caecum for the orthotopic model. Tumours were evaluated by histology, spectrofluorescence, MRI, and US. Results. Histology of CT26 tumour showed homogeneously dispersed cancer cells and blood vessels. The visualization of the vascular network using labelled albumin showed that CT26 tumours were highly vascularized and disorganized. MRI allowed high-resolution and accurate 3D tumour measurements and provided additional anatomical and functional information. Noninvasive US imaging allowed good delineation of tumours despite an hypoechogenic signal. Monitoring of tumour growth with US could be accomplished as early as 5 days after implantation with a shorter acquisition time (<5 min) compared to MRI. Conclusion. MRI and US afforded excellent noninvasive imaging techniques to accurately follow tumour growth of ectopic and orthotopic CT26 tumours. These two techniques can be appropriately used for tumour treatment followup, with a preference for US imaging, due to its short acquisition time and simplicity of use.

Quantitative imaging of nonlinear shear modulus by combining static elastography and shear wave elastography.

The study of new tissue mechanical properties such as shear nonlinearity could lead to better tissue characterization and clinical diagnosis. This work proposes a method combining static elastography and shear wave elastography to derive the nonlinear shear modulus by applying the acoustoelasticity theory in quasi-incompressible soft solids. Results demonstrate that by applying a moderate static stress at the surface of the investigated medium, and by following the quantitative evolution of its shear modulus, it is possible to accurately and quantitatively recover the local Landau (A) coefficient characterizing the shear nonlinearity of soft tissues.