Impact of Stretching on Tumor growth and Metastasis

National Institute Of Dental & Craniofacial Research

Investigators

Abstract

Breast cancer is a serious public health problem worldwide, representing the most frequent cancer among women, this situation urges multiple efforts to develop new more effective and less toxic treatments. There has been interest in developing non-pharmacological treatments that could boost natural defenses against cancer and contribute to primary and secondary cancer prevention. Among these, exercise has received a significant amount of attention due to the well-documented positive association between physical activity and survival in many cancer types. However, to date, physical modalities are not used specifically to modify the process of tumor formation. Animal studies of exercise in cancer models have yielded mixed results. Furthermore, these studies have involved levels of vigorous aerobic exercise that can be difficult to achieve in cancer patients. On the other hand, gentle movement-based techniques such as yoga, tai chi and qi gong are popular and well tolerated among cancer patients for managing symptoms and improving mobility and well-being. Stretching of tissues is a component of these techniques that has not been extensively studied but could have important effects on the cancer itself. Our recent studies show that gentle daily stretching for 10 minutes can have profound effects on reducing local connective tissue inflammation and fibrosis in several rodent models, via direct mechanical effects on the stretched tissues. We have also demonstrated a 52% reduction of mammary tumor growth over one month in mice undergoing stretching for 10 minutes once a day, without any other form of therapy. In this project, we will use this animal model aiming to: A) Explore the impact of stretching on tumor growth and the progression to metastasis. B) Investigate the mechanisms of the effect of stretching on tumor growth. The effect of Stretching will be tested in a polyoma middle T (MMTV-PyVmT) orthotopic mice breast cancer model, which is highly metastatic; we have started with the phase 1 of the project, aiming to establish the appropriate concentration of cells to be injected in the animals, with the tumor volume as the main outcome, which is being stablished by caliber and 3D ultrasound. Looking into the mechanism of Stretching, we have also conducted several preliminary tests coordinated with the imaging core facility at the NIDCR, to perform intravital microscopy experiments, to study the tumor stroma, architecture and vasculature, as well as the collagen organization in the surrounding matrix, using second-harmonic generation microscopy and track immune populations within the tumor and their interaction with the stroma, using fluorescent labelled probes by multiphoton confocal microscopy. Explore the impact of stretching on breast cancer cell lines grown in 3D culture: Using 3D culture could also contribute to understand the mechanism of stretching. We have used fibroblast populated collagen gels for ex vivo stretching experiments, obtaining a similar mechanoresponsive cell phenotype as compared to tissue explants. Our preliminary experiments using Met-1 cells derived from mammary carcinomas (MMTV-PyVmT) to populate collagen gels, show that after static stretching for 2h, Met- 1 cells increase their cell perimeter in response to stretch. The following strategies are in current development: Confirm these preliminary data, Explore the signaling cascade triggered by stretching by performing a phospho-array analysis focusing on selected targets (FAK signaling), Confirm identification of target by electrophoresis and western blot