Abstract
Haptotaxis, i.e., cell migration in response to adhesive gradients, has been previously implicated in cancer metastasis. A better understanding of cell migration dynamics and their regulation could ultimately lead to new drug targets, especially for cancers with poor prognoses, such as ovarian cancer. Haptotaxis has not been well-studied due to the lack of biomimetic, biocompatible models, where, for example, microcontact printing and microfluidics approaches are primarily limited to 2D surfaces and cannot produce the 3D submicron features to which cells respond. Here we used multiphoton excited (MPE) phototochemistry to fabricate nano/microstructured gradients of laminin (LN) as 2.5D models of the ovarian basal lamina to study the haptotaxis dynamics of a series of ovarian cancer cells. Using these models, we found that increased LN concentration increased migration speed and also alignment of the overall cell morphology and their cytoskeleton along the linear axis of the gradients. Both these metrics were enhanced on LN compared to BSA gradients of the same design, demonstrating the importance of both topographic and ECM cues on the adhesion/migration dynamics. Using two different gradient designs, we addressed the question of the roles of local concentration and slope and found that the specific haptotactic response depends on the cell phenotype and not simply the gradient design. Moreover, small changes in concentration strongly affected the migration properties. This work is a necessary step in studying haptotaxis in more complete 3D models of the tumor microenvironment for ovarian and other cancers.
Highlights
In 2013 there were an estimated 22,000 new cases of ovarian cancer in the United States and 15,000 deaths (Cancer Facts and Figures 2013, American Cancer Society, Database), where the five-year mortality rates for stage 3 and 4 cancers were ~80%–90%
Due to the suggested relevance of gradients in metastasis, we extended this work to examine the relationships between speed, cytoskeletal dynamics, gradient slope and metastatic potential
This study investigated the roles of local concentration and slope of gradients on cell migration dynamics using two gradient designs
Summary
In 2013 there were an estimated 22,000 new cases of ovarian cancer in the United States and 15,000 deaths (Cancer Facts and Figures 2013, American Cancer Society, Database), where the five-year mortality rates for stage 3 and 4 cancers were ~80%–90%. There remains a need for the development of more efficacious treatments to improve these outcomes Achieving all these goals require a better understanding of the underlying basic science of the tumor microenvironment (TME), for example, in terms of alterations of cell migration dynamics [1,2,3,4,5,6]. It is generally accepted that metastasis often occurs from exfoliation into ascites, and by reattachment in the intraperitoneal cavity (IP), interacting with mesothelial cells, and by invasion into the local stroma [7] These dynamics are generally regulated by matrix binding integrins (e.g., β1), matrix degrading proteinases (MMPs), and cell-cell adhesion molecules (cadherins). While mis-regulation of migration is generally associated with cancer invasion and metastasis, single genes have not typically been associated with enhanced migration and it has been speculated that different species act in concert [3]
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