Pre-Metastatic Niche: In Vivo Tissue Changes in Mechano-Structure by Chemotherapy-Induced Tumor-Derived Microparticles

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. 0.1-1 μm extracellular vesicles. The TMPs support tumor growth, e.g. by contributing to rapid mobilization of bone marrow derived proangiogenic cells (BMDCs) to the tumor site and likely also to potential metastatic sites. The BMDCs, with other local cells, can modify the microenvironment, making it more favorable to tumor cell seeding. Here, we evaluate effects of TMPs and TMPs from paclitaxel-treated breast cancer cells on physical and mechanical structure of potential pre-metastatic sites (i.e. lung, liver) in cancer-free mice.

We collected TMPs from growth media of murine 4T1 breast cancer cells, exposed to Paclitaxel or untreated controls. Taxol or untreated TMPs are injected into a mouse’s tail vain and PBS injection is used as a negative-control mouse-group. After several weeks, lungs and liver are harvested from the mice and 100 µm thick slices are cut by microtome. We measure the tissue-slice mechanics (e.g. elasticity and stiffness) of the three groups using shear rheometry.

Mouse lungs and liver are viscoelastic with combined liquid- and solid-like responses. The elasticity and viscosity is Taxol-TMP < untreated-TMP < control, and reduces under strain such that all samples reach similar mechanics under high (physiological) strain; Taxol-TMPs samples were significantly more uniform across slices and mice. We note that strain-induced changes in mechanics are mostly reversible, indicating that samples are unbroken, yet can potentially restructure differently; differences are smaller in the Taxol-TMP samples. Reduced resistance and increased reversibility under mechanical strain suggests changed ECM organization and structure under TMP-Taxol, which we also establish by changes in ECM composition and structure (e.g., collagen, fibronectin).

TMPs and especially chemotherapy induced TMPs induce mechano-structural changes in tissue (with no cancer in the body). Those changes may prepare tumor-favorable pre-metastatic niches, as escape-sites for tumor cells; thus, chemotherapy may potentially promote metastasis.