Abstract
The reciprocal interaction between circulating tumor cells (CTCs) and tissue-specific cells is influential for the progression of metastases. In particular, the process of extravasation relies on the complex cross-talk between cancer cells and other cellular players such as the endothelium and the secondary tissue. However, most in vitro studies only focus on one heterotypic cell-cell interaction and often lack of physiological relevance. In this project, we investigated both CTC-endothelium and CTC-secondary site interactions during cancer cell extravasation. We first used a microarray analysis of extravasated MDA-MB-231 breast cancer cells to identify key markers involved in extravasation. Then, we developed a tri-culture microfluidic platform combining cancer cells, endothelium and a bone-mimicking (BMi) microenvironment to assess how organ tropism influences the extravasation potential of cancer cells from different tissues. Through the microarray analyses of extravasated cancer cells we found that extravasation is associated with upregulation of late-metastatic markers along with specific proteases, such as matrix metalloprotease (MMP), a-disintegrin and metalloprotease (ADAM) and a-disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) family members, which are all involved in endothelium glycocalyx shedding. Through the microfluidic extravasation assay, we found that the bone-like microenvironment increased invasion and motility of breast, bladder and ovarian cancer cell (MDA-MB-231, T24 and OVCAR-3). Among the three cell types, ovarian cancer cells presented the lowest migration rate and bladder cancer cells the highest, hence recapitulating their different level of bone tropism observed in vivo. Taken together, our results shed light on the importance of intercellular communication between CTCs and other non-tumor cells essential for promoting cancer cell extravasation.
Highlights
Tumor metastasis is the primary cause of mortality among cancer patients, mainly caused by the resistance of disseminated cells to most current therapeutic agents [1]
Through the microarray analyses of extravasated cancer cells we found that extravasation is associated with upregulation of late-metastatic markers along with specific proteases, such as matrix metalloprotease (MMP), a-disintegrin and metalloprotease (ADAM) and a-disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) family members, which are all involved in endothelium glycocalyx shedding
Expression analysis on cancer cells migrating though micron-size constrictions have been previously reported [38], the originality of our study relies on the use of more physiologically-relevant samples, namely performing microarray analysis on cancer cells that have transmigrated through an endothelial monolayer
Summary
Tumor metastasis is the primary cause of mortality among cancer patients, mainly caused by the resistance of disseminated cells to most current therapeutic agents [1]. The first fundamental heterotypic interaction during this process happens with the adhesion (or physical trapping) of CTCs to the microvascular wall allowing cancer cells to transmigrate into the tissue parenchyma. Endothelial cells (ECs) are coated with a thin carbohydrate-rich structure called glycocalyx. It is composed of proteoglycans, glycoproteins and glycolipids associated with the plasma membrane [2]. Several processes are known to remodel and affect the glycocalyx, such as inflammation or changes in hemodynamic shear stress. During those events, degradation of the glycocalyx is triggered by exposure of the endothelium to extracellular proteases. The direct action of CTCs on the EC glycocalyx, notably regarding the proteases involved, has never been clearly demonstrated
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