Abstract
Cells receive mechanical cues from their extracellular matrix (ECM), which direct migration, differentiation, apoptosis, and in some cases, the transition to a cancerous phenotype. As a result, there has been significant research to develop methods to tune the mechanical properties of the ECM and understand cell-ECM dynamics more deeply. Here, we show that ionizing radiation can reduce the stiffness of an ex vivo tumor and an in vitro collagen matrix. When non-irradiated cancer cells were seeded in the irradiated matrix, adhesion, spreading, and migration were reduced. These data have ramifications for both in vitro and in vivo systems. In vitro, these data suggest that irradiation may be a method that could be used to create matrices with tailored mechanical properties. In vivo, these suggest that therapeutic doses of radiation may alter tissue mechanics directly.
Highlights
Radiation therapy is used on almost half of cancer patients as a method to cause cell death by damaging DNA.1 The effects of radiation on cell death are well established, but less is known about the effects of radiation on the extracellular matrix (ECM) residing within and surrounding tumors.Several studies have been performed to investigate the effects of ionizing radiation (IR) on the cellular microenvironment; much of this research uses models where the radiation is applied to a cellularized environment.2–5 In these cases, the effects of the radiation on the ECM and the effects of the radiation on the cells become difficult to isolate.The matrix within solid tumors is markedly different from the matrix within healthy tissue
The results revealed that stiffness is significantly reduced for irradiated tumors compared to untreated tumors and increasingly so with increased strain rates [Fig. 1(a)]
The tensile modulus of 5 mg/ml collagen irradiated in a single fraction of 63 Gy was compared with 6 doses of 10 Gy separated by 24 h and untreated gels
Summary
Radiation therapy is used on almost half of cancer patients as a method to cause cell death by damaging DNA. The effects of radiation on cell death are well established, but less is known about the effects of radiation on the extracellular matrix (ECM) residing within and surrounding tumors.Several studies have been performed to investigate the effects of ionizing radiation (IR) on the cellular microenvironment; much of this research uses models where the radiation is applied to a cellularized environment. In these cases, the effects of the radiation on the ECM and the effects of the radiation on the cells (which alter the ECM) become difficult to isolate.The matrix within solid tumors is markedly different from the matrix within healthy tissue. Several studies have been performed to investigate the effects of ionizing radiation (IR) on the cellular microenvironment; much of this research uses models where the radiation is applied to a cellularized environment.. Changes in the stiffness of the tumor microenvironment have been shown to be a contributing factor in cancer malignancy and metastasis.. Changes in the stiffness of the tumor microenvironment have been shown to be a contributing factor in cancer malignancy and metastasis.10–12 In light of these findings and others, there is significant interest in understanding how matrix stiffness changes during tumor progression, the effects of tissue stiffening on cells, and the development of therapeutics to inhibit or reverse stiffening. During tumor progression, increased extracellular matrix (ECM) deposition and cross-linking result in increased tumor stiffness. Changes in the stiffness of the tumor microenvironment have been shown to be a contributing factor in cancer malignancy and metastasis. In light of these findings and others, there is significant interest in understanding how matrix stiffness changes during tumor progression, the effects of tissue stiffening on cells, and the development of therapeutics to inhibit or reverse stiffening.
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