Abstract
Cancer cells exist in a mechanically and chemically heterogeneous microenvironment which undergoes dynamic changes throughout neoplastic progression. During metastasis, cells from a primary tumor acquire characteristics that enable them to escape from the primary tumor and migrate through the heterogeneous stromal environment to establish secondary tumors. Despite being linked to poor prognosis, there are no direct clinical tests available to diagnose the likelihood of metastasis. Moreover, the physical mechanisms employed by metastatic cancer cells to migrate are poorly understood. Because metastasis of most solid tumors requires cells to exert force to reorganize and navigate through dense stroma, we investigated differences in cellular force generation between metastatic and non-metastatic cells. Using traction force microscopy, we found that in human metastatic breast, prostate and lung cancer cell lines, traction stresses were significantly increased compared to non-metastatic counterparts. This trend was recapitulated in the isogenic MCF10AT series of breast cancer cells. Our data also indicate that increased matrix stiffness and collagen density promote increased traction forces, and that metastatic cells generate higher forces than non-metastatic cells across all matrix properties studied. Additionally, we found that cell spreading for these cell lines has a direct relationship with collagen density, but a biphasic relationship with substrate stiffness, indicating that cell area alone does not dictate the magnitude of traction stress generation. Together, these data suggest that cellular contractile force may play an important role in metastasis, and that the physical properties of the stromal environment may regulate cellular force generation. These findings are critical for understanding the physical mechanisms of metastasis and the role of the extracellular microenvironment in metastatic progression.
Highlights
While significant advances have been made in the treatment of primary tumors through surgery, chemotherapy and radiation treatment, a mechanism for effectively diagnosing the likelihood of metastasis remains elusive [1]
Metastatic cancer cells exert stronger traction forces To investigate the relationship between cellular traction force generation and metastatic potential, we examined the differences in traction force generation in three independent cancer models: breast, prostate, and lung cancer
Both the PC-3 highly metastatic prostate cancer cells (Fig. 1B) and the A549 metastatic lung cancer cells (Fig. 1C) exhibited significantly greater traction stresses than the non-metastatic PrEC primary prostate epithelial cells and the BEAS-2B lung epithelial cells, respectively. These data suggest that increasing force generation in cells of high metastatic potential may be a biophysical characteristic of metastatic cells that could potentially act as a mechanical marker for metastasis
Summary
While significant advances have been made in the treatment of primary tumors through surgery, chemotherapy and radiation treatment, a mechanism for effectively diagnosing the likelihood of metastasis remains elusive [1]. Studies have shown that a combination of genes can affect organ-specific tropism [9] These discoveries have generally not been applicable to multiple cancer types, or even within subtypes of a single cancer. While patients whose tumors contain these expression patterns will benefit from this kind of genetic analysis, it may not be applicable to a broad spectrum of patients with heterogeneous tumor populations. While these signatures may show significant statistical correlation with poor prognosis, they are not descriptive of the physical behaviors of the tumor cells that lead to these clinical results
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