From competency to dormancy: a 3D model to study cancer cells and drug responsiveness.

Josephine Y Fang,Ba X Hoang,Yi-Chen Wu,Bo Han,Zhi Yang,Shih-Jye Tan

doi:10.1186/s12967-016-0798-8

Josephine Y Fang, Ba X Hoang + Show 4 more

Open Access

https://doi.org/10.1186/s12967-016-0798-8

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Abstract

BackgroundThe heterogeneous and dynamic tumor microenvironment has significant impact on cancer cell proliferation, invasion, drug response, and is probably associated with entering dormancy and recurrence. However, these complex settings are hard to recapitulate in vitro.MethodsIn this study, we mimic different restriction forces that tumor cells are exposed to using a physiologically relevant 3D model with tunable mechanical stiffness.ResultsBreast cancer MDA-MB-231, colon cancer HCT-116 and pancreatic cancer CFPAC cells embedded in the stiffer gels exhibit a changed morphology and cluster formation, prolonged doubling time, and a slower metabolism rate, recapitulating the pathway from competency to dormancy. Altering environmental restriction allows them to re-enter and exit dormant conditions and change their sensitivities to drugs such as paclitaxol and gemcitabine. Cells surviving drug treatments can still regain competent growth and form tumors in vivo.ConclusionWe have successfully developed an in vitro 3D model to mimic the effects of matrix restriction on tumor cells and this high throughput model can be used to study tumor cellular functions and their drug responses in their different states. This all in one platform may aid effective drug development.

Highlights

The heterogeneous and dynamic tumor microenvironment has significant impact on cancer cell prolif‐ eration, invasion, drug response, and is probably associated with entering dormancy and recurrence
When cells were grown on mechanically tunable polyacrylamide gels, it has been found that hepatocellular carcinoma [16] and glioblastoma [38] cell proliferation rates were promoted by increasing of the matrix stiffness
We showed that the cell states of cancer cells have “On/Off ” states switched to fast growing or dormancy, but other states in between

Summary

Introduction

The heterogeneous and dynamic tumor microenvironment has significant impact on cancer cell prolif‐ eration, invasion, drug response, and is probably associated with entering dormancy and recurrence. These complex settings are hard to recapitulate in vitro. Solid tumors expose cells to a heterogeneous and complex extracellular matrix environment. Other extracellular matrix components such as laminin, fibronectin, tenascin have been observed in breast and primary small cell lung cancers in studies associated with cancer metastasis and drug resistance [8, 9]. LOX released from hypoxic tumor cells at the primary site are able to induce cross-linking of collagen and further increase matrix stiffness. In an in vivo study, the inoculated cancer cell proliferation was decreased in tumors generated from Mmp9-deficient mice compared to wild-type mice [14]

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