Abstract
AbstractThe invasion of cancer is brought about by continuous interaction of malignant cells with their surrounding tissue microenvironment. Investigating the remodeling of local extracellular matrix (ECM) by invading cells can thus provide fundamental insights into the dynamics of cancer progression. In this paper, we use an active untethered nanomechanical tool, realized as magnetically driven nanomotors, to locally probe a 3D tissue culture environment. We observed that nanomotors preferentially adhere to the cancer‐proximal ECM and magnitude of the adhesive force increased with cell lines of higher metastatic ability. We experimentally confirmed that sialic acid linkage specific to cancer‐secreted ECM makes it differently charged, which causes this adhesion. In an assay consisting of both cancerous and non‐cancerous epithelia, that mimics the in vivo histopathological milieu of a malignant breast tumor, we find that nanomotors preferentially decorate the region around the cancer cells.
Highlights
Cancer cells invade into their surrounding healthy tissues by degrading their surrounding extracellular matrix (ECM) and secreting fresh ECM.[1,2] The altered matrix microenvironment in turn deregulates the signaling within cancer cells, potentiating their invasion.[3,4] A strong interdependency exists between the ECM and cancer cells: mechanical properties of the ECM dysregulates signaling within cancerous cells, resulting in aberrant expression of matrix and matricellular proteins, which in turn can alter the chemical and physical composition of the ECM
Our observations were consistent across four distinct breast cancer cell lines, which suggests this observation may be applicable across malignant tumors of other organs as well
We find that the physical effects of invading cancer cells manifest up to a length of % 40 mm from the cell surface within the ECM surrounding them
Summary
Cancer cells invade into their surrounding healthy tissues by degrading their surrounding extracellular matrix (ECM) and secreting fresh ECM.[1,2] The altered matrix microenvironment in turn deregulates the signaling within cancer cells, potentiating their invasion.[3,4] A strong interdependency exists between the ECM and cancer cells: mechanical properties of the ECM dysregulates signaling within cancerous cells, resulting in aberrant expression of matrix and matricellular proteins, which in turn can alter the chemical and physical composition of the ECM. The cells were embedded within a reconstituted basement membrane (rBM) matrix, which mimics the ECM that breast cancer epithelia interact with, degrade and replace with freshly synthesized collagenous ECM during invasion.[23] The injected nanomotors ( referred to as nanorobots or nanopropellers in literature) were subjected to rotating magnetic fields, where the chiral shape caused the rotating nanomotors to move forward or backward, depending on the handedness of the helix and sense of rotation of the field This method[24,25,26,27] of remote manipulation of untethered nanomotors has been shown to be more efficient[28] than conventional magnetic gradient pulling methods at small length scales. These differences between cancer cells and surrounding normal cells make important contributions to our knowledge of the heterogeneity of tumor microenvironment
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