Cancer mechanobiology is the study of how physical and mechanical forces affect how cancer cells behave, develop, and progress.

As scientists have come to understand the critical role that mechanical cues from the cellular microenvironment play in the initial development, invasion, and metastasis of cancer, this topic has recently attracted a lot of attention. Cell-cell interactions, extracellular matrix (ECM) stiffness, blood flow, and tissue compression are the four main mechanical forces that exist in tissues and organs.

These mechanical forces affect the way cancer cells behave by interacting with them in three major ways:

1. Migration and Invasion

Mechanical factors can direct the migration and invasion of cancer cells into neighbouring tissues. Cells are able to detect variations in ECM stiffness and move toward softer places using these cues. Durotaxis is the name for this process. Cancer cells can also produce pressures that weaken the ECM, which enables them to penetrate nearby tissues.

2. Metastasis

A crucial aspect of cancer growth is the capacity of cancer cells to separate from the primary tumour, enter the circulation, and form new tumours in distant organs. Cancer cell intravasation (entering blood vessels) and extravasation (exiting blood vessels) during metastasis are influenced by mechanical forces in blood vessels and tissues.

3. Tumor proliferation and angiogenesis

Mechanical cues from the surrounding microenvironment can influence the development and proliferation of cancer cells. Softer ECM may hinder cancer cell division, but stiffer ECM may encourage it. The development of blood vessels within tumours, which is necessary for their growth and survival, can also be influenced by mechanical forces.

By utilizing the understanding of how mechanical forces and physical signals affect cancer cells, we can use cancer mechanobiology to develop new methods for early detection, prognosis evaluation, and cutting-edge therapeutic approaches. Here are some ways that these fields can use cancer mechanobiology:

1. Using Mechanobiology to Detect & Diagnose Early Stages of Cancer

As cancer progresses, mechanical characteristics of tissues, such as stiffness, might change. Identifying changed biomechanical qualities in tissues can be aided by methods like atomic force microscopy (AFM), which evaluates the stiffness of the tissue. These alterations may act as biomarkers for the early diagnosis of malignancy. In addition, compared to healthy cells, cancer cells frequently show different mechanical characteristics. Using microfluidic tools, it may be possible to identify cancer cells that are circulating in the bloodstream by analysing the deformability of individual cells.

2. Using Mechanobiology to Evaluate Cancer Prognosis and Disease Progression

A tumour’s stiffness, which reflects its mechanical characteristics, can reveal information about how aggressive it is and whether it has the ability to metastasize. A more advanced disease stage may be indicated by tumours with increased rigidity. Tumor stiffness can be measured using imaging techniques such as magnetic resonance elastography or ultrasound elastography. Furthermore, investigating the mechanical cues present in the tumour microenvironment can aid in determining the likelihood of cancer being aggressive. Collagen fibre alignment and organization can affect tumour behaviour, as can other elements including fluid flow patterns.

3. Using Mechanobiology to Develop Cutting-edge Therapeutic Approaches

By comprehending the mechanosensitive signalling pathways in cancer cells, researchers can create treatments that disrupt these pathways. It is possible to slow the spread of cancer by inhibiting the processes which promote invasion and metastasis. This can entail concentrating on mechanotransduction-related proteins or causing focal adhesions to break down. In addition, mechanical stimulation of tumours or cancerous cells can have therapeutic effects. For instance, radiation therapy’s mechanical stress can increase its effectiveness. As another potential therapy option, using microenvironments with a particular stiffness to direct cancer cell behaviour can be investigated. Furthermore, the efficiency of drug delivery might be impacted by the mechanical characteristics of the tumour. Higher-stiffness tumours may have less medication penetration. Drug delivery and efficacy can be improved by creating drug delivery systems that are responsive to the mechanical characteristics of the tumour microenvironment.

2D soft hydrogels for the study of cancer mechanobiology

Earlier studies have shown that changes in ECM stiffness modulate tumour malignancy. Levental and colleagues (2009) demonstrated that collagen crosslinking influences ECM remodelling and stiffening which promotes breast tumorigenesis. Conversely, inhibiting collagen crosslinking decreases matrix stiffening and tumour incidence. Subsequently, there have been many studies employing the use of 2D soft hydrogels to study cancer metastasis.  2D soft hydrogels offer several advantages due to their ability to mimic the physiological and mechanical properties of native tissues. As opposed to 3D culture, 2D soft hydrogels offer more precise control over culture conditions. Researchers can easily manipulate the mechanical properties, stiffness gradients, and other parameters of the hydrogel to create specific experimental setups. 2D soft hydrogels are easy to fabricate and are often easier to standardize and reproduce across experiments, leading to more consistent results. 2D soft hydrogels are also amenable to high-throughput screening and imaging-based assays. In a study by Bertero and colleagues (2019), Matrigen Softwells of 1 and 8 kPa stiffness were used to mimic the physiological and pathophysiological ECM respectively. The study showed that ECM stiffening mechanoactivates the metabolism of glutamine and glycolysis, coordinating the transit of non-essential amino acids within the tumour niche and supporting tumour growth and metastasis. Watson and colleagues (2021) also used Matrigen Softwells with two different stiffness (0.5 kPa for soft tissue and 8.0 kPa for stiff breast tumours) to investigate the mechanoresponse of the breast cancer cell lines and patient-derived xenograft primary cells. They found that fibrotic-like matrix stiffness promotes specific metastatic behaviours that are maintained in cancer cells after the transition to softer microenvironments like bone marrow. All-in-all, 2D soft hydrogels are valuable tools to mimic ECM stiffness to study the effects of mechanical cues on cancer cell behaviour.

References 

1. Bertero T, Oldham WM, Grasset EM, Bourget I, Boulter E, Pisano S, Hofman P, Bellvert F, Meneguzzi G, Bulavin DV, Estrach S, Feral CC, Chan SY, Bozec A, Gaggioli C. Tumor-Stroma Mechanics Coordinate Amino Acid Availability to Sustain Tumor Growth and Malignancy. Cell Metab. 2019 Jan 8;29(1):124-140.e10.
2. Chaudhuri PK, Low BC, Lim CT. Mechanobiology of Tumor Growth. Chem Rev. 2018 Jul 25;118(14):6499-6515.
3. Lee G, Han SB, Lee JH, Kim HW, Kim DH. Cancer Mechanobiology: Microenvironmental Sensing and Metastasis. ACS Biomater Sci Eng. 2019 Aug 12;5(8):3735-3752.
4. Levental KR, Yu H, Kass L, Lakins JN, Egeblad M, Erler JT, Fong SF, Csiszar K, Giaccia A, Weninger W, Yamauchi M, Gasser DL, Weaver VM. Matrix crosslinking forces tumor progression by enhancing integrin signaling. Cell. 2009 Nov 25;139(5):891-906.
5. Papavassiliou KA, Basdra EK, Papavassiliou AG. The emerging promise of tumour mechanobiology in cancer treatment. Eur J Cancer. 2023 Sep;190:112938. doi: 10.1016/j.ejca.2023.112938. Epub 2023 Jun 9. PMID: 37390803.
6. Rao J, Lim CT, Hu T, Han D. Editorial: Cancer Cell Mechanobiology – A New Frontier for Cancer Invasion and Metastasis Research. Front Cell Dev Biol. 2021 Oct 7;9:775012.
7. Watson AW, Grant AD, Parker SS, Hill S, Whalen MB, Chakrabarti J, Harman MW, Roman MR, Forte BL, Gowan CC, Castro-Portuguez R, Stolze LK, Franck C, Cusanovich DA, Zavros Y, Padi M, Romanoski CE, Mouneimne G. Breast tumor stiffness instructs bone metastasis via maintenance of mechanical conditioning. Cell Rep. 2021 Jun 29;35(13):109293.
8. Yoon CW, Pan Y, Wang Y. The application of mechanobiotechnology for immuno-engineering and cancer immunotherapy. Front Cell Dev Biol. 2022 Nov 22;10:1064484.
9. Zhang SX, Liu L, Zhao W. Targeting Biophysical Cues: a Niche Approach to Study, Diagnose, and Treat Cancer. Trends Cancer. 2018 Apr;4(4):268-271.
10. Zuela-Sopilniak N, Lammerding J. Engineering approaches to studying cancer cell migration in three-dimensional environments. Philos Trans R Soc Lond B Biol Sci. 2019 Aug 19;374(1779):20180219.