Research Papers

The Solid Mechanics of Cancer and Strategies for Improved Therapy

[+] Author and Article Information
Triantafyllos Stylianopoulos

Cancer Biophysics Laboratory,
Department of Mechanical and
Manufacturing Engineering,
University of Cyprus,
Nicosia, 1678, Cyprus
e-mail: tstylian@ucy.ac.cy

Manuscript received June 1, 2016; final manuscript received October 6, 2016; published online January 19, 2017. Assoc. Editor: Carlijn V.C Bouten.

J Biomech Eng 139(2), 021004 (Jan 19, 2017) (10 pages) Paper No: BIO-16-1230; doi: 10.1115/1.4034991 History: Received June 01, 2016; Revised October 06, 2016

Tumor progression and response to treatment is determined in large part by the generation of mechanical stresses that stem from both the solid and the fluid phase of the tumor. Furthermore, elevated solid stress levels can regulate fluid stresses by compressing intratumoral blood and lymphatic vessels. Blood vessel compression reduces tumor perfusion, while compression of lymphatic vessels hinders the ability of the tumor to drain excessive fluid from its interstitial space contributing to the uniform elevation of the interstitial fluid pressure. Hypoperfusion and interstitial hypertension pose major barriers to the systemic administration of chemotherapeutic agents and nanomedicines to tumors, reducing treatment efficacies. Hypoperfusion can also create a hypoxic and acidic tumor microenvironment that promotes tumor progression and metastasis. Hence, alleviation of intratumoral solid stress levels can decompress tumor vessels and restore perfusion and interstitial fluid pressure. In this review, three major types of tissue level solid stresses involved in tumor growth, namely stress exerted externally on the tumor by the host tissue, swelling stress, and residual stress, are discussed separately and details are provided regarding their causes, magnitudes, and remedies. Subsequently, evidence of how stress-alleviating drugs could be used in combination with chemotherapy to improve treatment efficacy is presented, highlighting the potential of stress-alleviation strategies to enhance cancer therapy. Finally, a continuum-level, mathematical framework to incorporate these types of solid stress is outlined.

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Fig. 3.

Residual solid stress: (a) evidence of growth-induced, residual stress. A cut along the long axis of a tumor results in swelling of the interior and opening of the periphery of the tumor, (b) tumor opening measurements in murine and human tumors. Tumor opening is normalized by division with the diameter of the tumor (reproduced with permission from Ref. [9]), (c) tumor opening increases with the volume of the tumor for three cancer cell lines, human melanoma Mu89, pancreatic adenocarcinoma AK4.4, and mammary adenocarcinoma 4T1 (adapted with permission from Ref. [6]), and (d) selective depletion of cancer cells, human CAFs (hCAFs), collagen, or hyaluronan decreases significantly tumor opening in melanoma (Mu89), breast (4T1, E0771), and pancreatic (AK4.4) tumors, indicative of stress alleviation. (Adapted with permission from Ref.[9].)

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Fig. 2.

Swelling solid stress: (a) schematic of the protocol for measuring swelling stress in tumors utilizing the confined compression experiment and modulated the electrolyte concentration of the tumor interstitial space, (b) swelling stress measurements as a function of NaCl concentration in two orthotopic breast tumor models (MCF10CA1a and 4T1), Swelling stress as a function of (c) hyaluronan, (d) collagen, and (e) hyaluronan to collagen content.

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Fig. 1.

Externally applied solid stress: (a) schematic of externally applied stress at the tumor center and periphery, (b) mathematical model predictions of the spatial profile of radial and circumferential components of solid stress in tumors, and (c) histological sections of human tumors show the deformation of tumor blood vessels. Top: salivary duct carcinoma (left), undifferentiated liposarcoma (right), bottom: differentiated pancreatic neuroendocrine tumors. Arrows show tumor location. (scale bar = 100 μm). (Adapted with permission from Ref. [6]).

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Fig. 4.

Schematic of stress alleviation treatments. Selective depletion of cancer cells, fibroblasts, collagen, or hyaluronan can result in stress alleviation and blood vessel decompression improving vessel functionality. (Reproduced with permission from Ref. [9].)

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Fig. 5.

Stress alleviation strategy improves perfusion in hypovascular orthotopic pancreatic AK4.4 and Capan2 tumors. (a and b) Fluorescence images showing increased number of perfused vessels in saridegib-treated tumors. Cd31 (green color) stains for all tumor vessels, while lectin (red color) stains only perfused vessels. (c–f) Saridegib alleviates solid stress showed by the decrease in the tumor opening, decompresses both blood and lymphatic vessels, improves fraction of perfused vessels, without affected vascular density. +, saridegib; −, vehicle. The asterisks denote a statistically significant difference. (Reproduced with permission from Ref. [9].)




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