Solid stress and elastic energy as measures of tumour mechanopathology

Nia, Hadi Tavakoli; Liu, Hao; Seano, Giorgio; Datta, Meenal; Jones, Dennis; Rahbari, Nuh N.; Incio, João; Chauhan, Vikash P.; Jung, Keehoon; Martin, John D.; Askoxylakis, Vasileios; Padera, Timothy P.; Fukumura, Dai; Boucher, Yves; Hornicek, Francis J.; Grodzinsky, Alan J.; Baish, James W.; Munn, Lance L.; Jain, Rakesh K.

doi:10.1038/s41551-016-0004

Cited by 334 publications

(378 citation statements)

References 46 publications

(54 reference statements)

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“…The resulting range of elastic moduli of 1.5 to 7.5 kPa (assuming E = 3xG’) from these studies is physiologically relevant, as it is similar to the range of stiffening previously reported in mouse models of pancreatic ductal adenocarcinoma [32]. Solid tumors also show an increase in elastic energy, independent of stiffness [33]. This mechanically-tunable aECM provides a facile approach for investigating the roles of both stiffness and viscoelasticity on cellular behavior.…”

Section: Discussionsupporting

confidence: 72%

Sequential modes of crosslinking tune viscoelasticity of cell-instructive hydrogels

2019

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Materials that can mimic the fibrillar architecture of native extracellular matrix (ECM) while allowing for independent regulation of viscoelastic properties may serve as ideal, artificial ECM (aECM) to regulate cell functions. Here we describe an interpenetrating network of click-functionalized alginate, crosslinked with a combination of ionic and covalent crosslinking, and fibrillar collagen type I. Varying the mode and magnitude of crosslinking enables tunable stiffness and viscoelasticity, while altering neither the hydrogel’s microscale architecture nor diffusional transport of molecules with molecular weight relevant to typical nutrients. Further, appropriately timing sequential ionic and covalent crosslinking permits self-assembly of collagen into fibrillar structures within the network. Culture of human mesenchymal stem cells (MSCs) in this mechanically-tunable ECM system revealed that MSC expression of immunomodulatory markers is differentially impacted by the viscoelasticity and stiffness of the matrix. Together, these results describe and validate a novel material system for investigating how viscoelastic mechanical properties of ECM regulate cellular behavior.

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Section: Discussionsupporting

confidence: 72%

Sequential modes of crosslinking tune viscoelasticity of cell-instructive hydrogels

2019

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“…We subsequently showed that losartan and lisinopril, an angiotensin converting enzyme inhibitor (ACEi), decreased not only collagen but also hyaluronan, and enhanced the efficacy of low molecular weight chemotherapeutics in desmoplastic mice tumors(6). This benefit was in part due to the decompression of blood vessels resulting from decreased solid stress(7,8). The safety and low cost of ARBs and ACEis, together called angiotensin system inhibitors (ASIs), along with their potentiation of conventional chemotherapy make a strong case for repurposing ASI as adjuncts in cancer treatment.…”

Section: Introductionmentioning

confidence: 99%

Use of Angiotensin System Inhibitors Is Associated with Immune Activation and Longer Survival in Nonmetastatic Pancreatic Ductal Adenocarcinoma

Liu

Naxerova

Pinter

et al. 2017

Clinical Cancer Research

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Purpose Angiotensin system inhibitors (ASIs) can improve prognosis in multiple cancer types, including pancreatic ductal adenocarcinoma (PDAC). However, no study has examined the effect of ASIs alone or combined with adjuvant chemotherapy in resected PDAC patients. Experimental Design We performed an analysis of the records of ASI users and non-user patients with PDAC seen at Massachusetts General Hospital between January 2006 and December 2010. To identify mechanisms of ASIs in PDAC, we performed RNA-Seq of resected primary lesions. Results 794 consecutive patients were included. In 299 resected patients, ASI-users experienced longer overall survival (OS) in both univariate (median OS: 36.3 vs. 19.3 months, p=0.011) and adjusted multivariate (HR, 0.505; 95%CI, 0.339 - 0.750; p=0.001) analyses. Propensity score adjusted analysis also showed a longer median OS for chronic ASI-users. In unresected patients, the beneficial effect of ASIs was significant in patients with locally advanced disease, but not in metastatic patients. RNA-Seq analysis revealed in tumors of ASI-users (lisinopril) a normalized extracellular matrix, a reduced expression of genes involved in PDAC progression (e.g. WNT and Notch signaling) and an increased expression of genes linked with the activity of T cells and antigen-presenting cells. Finally, chronic use of ASI was associated with a gene expression signature which is predictive of survival in independent validation cohorts. Conclusions In patients with non-metastatic PDAC, chronic ASI use is associated with longer OS independently of chemotherapy. Our RNA-Seq analysis suggests that ASI reduce the malignant potential of cancer cells and stimulate the immune microenvironment in primary PDAC.

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“…Alterations in the ECM together with proliferating tumour and stromal cells leads to accumulation of independent of IFP, which compress vessels 29,40,41 . These forces have been quantified using mathematical modelling and 41,42 . Depletion of tumour cells, cancer-associated fibroblasts (CAFs), or ECM showed that all three components contribute to solid stress accumulation in tumours in mice 40,41 .…”

Section: Physical Microenvironment Of the Tumourmentioning

confidence: 99%

Engineering and physical sciences in oncology: challenges and opportunities

2017

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The principles of engineering and physics have been applied to oncology for nearly 50 years. Engineers and physical scientists have made contributions to all aspects of cancer biology, from quantitative understanding of tumour growth and progression to improved detection and treatment of cancer. Many early efforts focused on experimental and computational modelling of drug distribution, cell cycle kinetics and tumour growth dynamics. In the past decade, we have witnessed exponential growth at the interface of engineering, physics and oncology that has been fuelled by advances in fields including materials science, microfabrication, nanomedicine, microfluidics, imaging, and catalysed by new programmes at the National Institutes of Health (NIH), including the National Institute of Biomedical Imaging and Bioengineering (NIBIB), Physical Sciences in Oncology, and the National Cancer Institute (NCI) Alliance for Nanotechnology. Here, we review the advances made at the interface of engineering and physical sciences and oncology in four important areas: the physical microenvironment of the tumour and technological advances in drug delivery; cellular and molecular imaging; and microfluidics and microfabrication. We discussthe research advances, opportunities and challenges for integrating engineering and physical sciences with oncology to develop new methods to study, detect and treat cancer, and we also describe the future outlook for these emerging areas.

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Solid stress and elastic energy as measures of tumour mechanopathology

Cited by 334 publications

References 46 publications

Sequential modes of crosslinking tune viscoelasticity of cell-instructive hydrogels

Sequential modes of crosslinking tune viscoelasticity of cell-instructive hydrogels

Use of Angiotensin System Inhibitors Is Associated with Immune Activation and Longer Survival in Nonmetastatic Pancreatic Ductal Adenocarcinoma

Engineering and physical sciences in oncology: challenges and opportunities

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