Cell‐Taxi: Mesenchymal Cells Carry and Transport Clusters of Cancer Cells

Abstract

The migration of cancer cell groups is highly dependent on the chemical and physical guidance cues provided by the tumor stroma, which polarize cell collectives and enable their coordinated movement. For example, macrophages attracted by cancer cells can stimulate the multicellular streaming of tumor cells. [7] Moreover, activated fibroblasts in tumor stroma exert forces on cancer cells [8] and create tracks [9] in extracellular matrix (ECM) or align collagen fibers, [10] which promote efficient directional migration of groups of cancer cells along these features. The movement of cohesive multicellular groups is generally led by an invasive leader cell, which creates a path and sets the direction of migration for non-invasive follower cells in the group. [11] Once the groups of cancer cells invade the vasculature, they can dynamically reorganize and adjust their geometries to pass even through narrow blood vessels. [12] These multicellular groups, also known as circulating tumor cell clusters (CTCCs), can contain between 4 -100 cells. [12] However, CTCCs found in the bloodstream of cancer patients are not composed solely of cancer cells and may also contain mesenchymal cells, endothelial cells, and/or immune cells. [13] Clusters of mesenchymal cells with cancer cells have been detected in the peripheral blood of patients with metastatic breast cancer but not in the blood of healthy donors. The presence of circulating CAFs in the blood was confirmed in 88% of patients with metastatic disease and only in 23% of patients with localized breast cancer. [14] Similarly, increased numbers of circulating mesenchymal cells correlated with a worse prognosis and a lower probability of survival in metastatic patients. [15] The importance of co-traveling mesenchymal/ stromal cells in the metastatic process is also supported by observations that up to 86% of carcinoma cells that spread to the lungs were accompanied by primary tumor stroma-derived cells; in the majority of cases, these cells stained positive for smooth muscle α-actin (α-SMA) but only 28% cases stained positive for F4/80, a macrophage marker. [16] When the tumor stromal cells were partially depleted, the number of metastases significantly decreased.While mesenchymal stromal cells (MSCs) are known to be recruited to damaged or inflamed tissue, where they promote tissue regeneration, MSCs are also attracted to tumor sites. [17][18][19] Currently, without lineage tracing experiments, it is difficult to Cell clusters that collectively migrate from primary tumors appear to be far more potent in forming distant metastases than single cancer cells. A better understanding of the collective cell migration phenomenon and the involvement of various cell types during this process is needed. Here, an in vitro platform based on inverted-pyramidal microwells to follow and quantify the collective migration of hundreds of tumor cell clusters at once is developed. These results indicate that mesenchymal stromal cells (MSCs) or cancer-associated fibroblasts (CAFs) in the heterotypi...

Tunable hybrid hydrogels with multicellular spheroids for modeling desmoplastic pancreatic cancer

“…They used an equal ratio of fibroblasts to cancer cells. In another study, cancer cell to stromal cell ratios of 10:1 to 1:10 was tested and the higher CAF ratios showed higher Young's moduli [ 31 ]. However, when the compactness was compared of two cancer cell lines they have used, one responded to increased stromal cell ratio with increased compactness, on the other hand another cell line showed no change in spheroids compactness.…”