Lung Mechanics Change in Response to Chemotherapy-Induced Tumor-Derived Microparticles

Introduction

The mechanics of the tumor microenvironment greatly affects the cell and whole tumor growth rate, the tumor cells’ invasive capacity, and their survival following treatment. Following chemotherapy, tumor cells respond by shedding increased numbers of tumor-derived microparticles (TMPs), i.e. 0.1-1μm extracellular vesicles. Those TMPs support tumor growth, for example, by contributing to a rapid mobilization of bone marrow derived proangiogenic cells (BMDCs) towards the treated tumor site and likely also to potential metastatic sites. The BMDCs, with other local cells, are able to modify the microenvironment, making it more favorable to tumor cell seeding. However, the physical and mechanobiological changes in the pre-metastatic sites which support tumor cell seeding have not been determined. Here, we have evaluated the effects of TMPs shed from breast cancer cells and TMPs treated with paclitaxel on rheology of organs in cancer-free mice.

Materials and methods

We collected TMPs from the growth media of murine 4T1 breast cancer cells that were exposed in vitro to Paclitaxel and from untreated control cells. The collected TMPs are injected into the mice tail vain and a negative-control group is added where PBS is injected. After several weeks, we harvest the lungs and liver from each mouse and 100µm thick slices are cut by microtome. We measure various mechanical properties (e.g. elasticity and stiffness) of the tissue slices using shear rheometry.

Results and discussion

We observe that mouse lungs are in general viscoelastic with mucosal-like rheology. Following the in vivo exposure to control TMPs, we observe a wide range of stiffness both between mice and within slices from the same mouse; this shows the heterogeneity of the lung structure. In contrast, in lung slices from mice exposed to chemotherapy-induced TMPs we observe reduced and more homogenous stiffness. Furthermore, we observe statistically significant differences in the plastic-like damage induced in the different samples when physiological-level deformations are induced; those relate e.g. to normal and heavy breathing cycles. Specifically, lungs the chemotherapy-induced TMPs are more resilient and elastic, returning to similar values.

Conclusion

TMP induced changes in tissue independently of cancer may indicate preparation of tumor-favorable pre-metastatic niches at distant sites.