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Brás, M.; Sousa, S.R.; Carneiro, F.; Radmacher, M.; Granja, P. Mechanobiology of Colorectal Cancer. Encyclopedia. Available online: https://encyclopedia.pub/entry/22158 (accessed on 21 April 2024).
Brás M, Sousa SR, Carneiro F, Radmacher M, Granja P. Mechanobiology of Colorectal Cancer. Encyclopedia. Available at: https://encyclopedia.pub/entry/22158. Accessed April 21, 2024.
Brás, Manuela, Susana R Sousa, Fátima Carneiro, Manfred Radmacher, Pedro Granja. "Mechanobiology of Colorectal Cancer" Encyclopedia, https://encyclopedia.pub/entry/22158 (accessed April 21, 2024).
Brás, M., Sousa, S.R., Carneiro, F., Radmacher, M., & Granja, P. (2022, April 22). Mechanobiology of Colorectal Cancer. In Encyclopedia. https://encyclopedia.pub/entry/22158
Brás, Manuela, et al. "Mechanobiology of Colorectal Cancer." Encyclopedia. Web. 22 April, 2022.
Mechanobiology of Colorectal Cancer
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It is well documented that colorectal cancer (CRC) is the third most common cancer type, responsible for high mortality in developed countries, resulting in a high socio-economic impact. Several biochemical and gene expression pathways explaining the manifestation of this cancer in humans have already been identified. However, explanations for some of the related biophysical mechanisms and their influence on CRC remain elusive. In CRC, biophysics and medical research have already revealed the importance of studying the effects of the stiffness and viscoelasticity of the substrate on cells, as well as the effect of the shear stress of blood and lymphatic vessels on the behavior of cells and tissues. A deeper understanding of the relationship between the biophysical cues and biochemical signals could be advantageous to develop new diagnostic techniques and therapeutic strategies. Being a disease with a high mortality rate, it becomes crucial to dedicate efforts to finding effective, alternative therapeutic strategies. 

colorectal cancer biophysical cues biochemical pathways mechanobiology atomic force microscopy

1. A Brief Introduction to Colorectal Cancer (CRC)

Sung et al. presented the cancer incidence and mortality provided by the International Agency for Research on Cancer (IARC) at GLOBOCAN 2020. Worldwide, breast cancers present the highest number of new cases (11.7%), followed by lung (11.4%) and CRC (10.0%). Lung cancer was the leading cause of cancer death (18%), followed by CRC (10%). In summary, CRC is the third in terms of incidence but the second in terms of mortality [1][2].
The risk of CRC has been growing over the past few years due to environmental factors, a sedentary lifestyle, and diet [3]. Shussman and Wexner referred that multiple, cumulative genetic alterations lead to the formation of a neoplastic process, normally explained taking into consideration molecular biology and biochemical phenomena, and frequently not through biophysics, in which the forces exerted by the cells and the ECM are translated into biochemical signals (mechanotransduction) [4]. A deeper understanding of biophysical mechanisms behind biochemical pathways can lead to the development of new therapeutic strategies. For that purpose, it is important to understand the influence of several physical cues, such as: (i) internal forces of the cells; (ii) forces produced by the neighboring cells; (iii) forces coming from interstitial spaces (such as mechanical tension, compression, and hydrostatic pressure); (iv) forces resulting from the alterations of ECM stiffness; (v) shear stress (the parallel force per unit area applied to cell walls) from the fluid flow (such as blood); and (vi) forces from adhesion molecules [5]. Understanding the role of biophysical cues makes it possible to evaluate which biomechanical response will be activated. Each response will induce changes in CRC cell behavior (increased motility, shape changes, stiffness changes) which can promote the CRC cell motility, migration, invasion, extravasation, and metastization. The origin of adenocarcinomas, as well as the large intestine tissue with its several different cell types and functions has already been well described in the literature [3][4][6][7][8][9].
Not every CRC shares similar driving mutations, making it extremely difficult to design a general molecular therapy [10]. Surgery is the initial approach in terms of treatment if an early diagnosis is performed. However, if it has already been metastasized, this approach is not effective anymore. These patients also develop drug resistance, and the recurrence of cancer is very common [11].

2. Mechanobiology in CRC Therapeutics

Conventional therapies, such as chemotherapy and radiotherapy, have been developed based on biological and biochemical knowledge of cancer cells. However, physical properties have emerged as playing an important role to fight cancer. These conventional treatments have the disadvantages of affecting not only tumor cells, but inducing undesirable collateral effects in healthy cells and tissues. Cell membranes and the cytoskeleton of cancer cells are targeted by chemotherapeutic agents, inducing cytotoxicity and altering the adherence process. The effects of chemotherapy usually rely on altered cell mechanics and may lead to vascular complications. The causes of those complications are related to mechanical obstructions of blood vessels from the main organs. The obstruction is caused by the increase of circulating leukemia cells, as well as the increase of cyto-adherence and stiffness [12]. The only advantage of conventional treatments is that they show fast results (independently if they were efficient or not) and, if they are not efficient, clinicians may quickly change the drug (or combinations of drugs).
The biophysical effects (elastic changes) of chemotherapy were studied on acute lymphoblastic leukemia and acute myeloid leukemia cells (removed from peripheral blood or bone marrow of 8–78-year-old patients) [13]. Both cell types were treated with dexamethasone and daunorubicin. Nanoindentation assays by AFM showed that leukemia cells exhibited doubled stiffness values during cell death [13]. Cells taken from the patients but not exposed to chemotherapeutic drugs did not show significant changes in their elastic moduli. The stiffness increase seems to result from the reorganization of the actin microfilaments, due to the polymerization and depolymerization, during apoptosis [14][15].
Immunotherapy has the advantage of reinforcing the immunological system based on antibodies, vaccines, and adoptive therapies. The disadvantage is that results are not so quick as those obtained with chemotherapy and/or radiotherapy. Some cancers do not respond to immunotherapy [16]. The combination of immunology with biophysical studies has led to mechanoimmunology [17]. Chimeric antigen receptor-T cell (CAR-T) constitutes a promising method to recruit T-cells to fight cancer cells. The CAR-T is separated in the CAR-T intracellular domain and its plasma membrane, due to mechanical forces produced by membrane motions, which activate signaling processes. The CAR-T has been mentioned to be helpful when joined to hematology malignancies. This molecule is also interesting to be used in solid tumors, such as CRC. The objective is to promote the binding of T-cells to different antigens of the CRC cells [18]. AFM could be a suitable methodology to study the specific bindings of CAR-T cells and the tumor molecules. AFM single-cell force spectroscopy can be used to study the binding of the CAR-T and eventual antigens that could exist in CRC cells. Kristi et al. used AFM to characterize the molecular interaction forces between the immune cells system and the antigen-presenting cell [17]. Lysophosphatidic acid (LPA) is a ligand for cell surface receptors. CRC cells demonstrate an aberrant expression of LPA receptors, contributing to tumorigenesis through the increase of inflammatory responses [19]. High levels of LPA2 are expressed by human CRC tissues compared with corresponding healthy colonic tissues. In adenocarcinomas of the colon, the LPA1 expression is lower [20]. With the LPA receptors being very important in colon cancer, they should be one of the targets in terms of the development of new therapies, i.e., new antibodies that could block the LPA binding receptor or new therapeutics that stop the gene pathway responsible for the LPA expression. AFM is a powerful tool, since the probe can be functionalized with molecules such as antibodies to study the specific target receptors.
Cortes et al. using AFM nanoindentation (through measurement of elasticity), found that when a specific drug was used to treat pancreatic ductal adenocarcinoma, cell stiffness was reduced, thereby suppressing cell invasion [21].
CTCs provide information about physical (size, density) or biological (tumor markers) parameters found in the patient’s blood [22][23][24].
The SW480 cell line treated with fullerenol was studied by Liu et al. using AFM to demonstrate the morphological and mechanical changes [25][26]. The Young’s modulus was used together with the adhesion force to infer the resistance of cells to the administered drug. The multinuclear cells, treated and untreated with two different concentrations of the drug, showed similar characteristics regarding their height, length, width, and roughness. For mononuclear cells, the distribution of those parameters was significantly different. The authors observed that multinuclear cells are more resistant to the fullerenol when compared with the mononuclear ones [27].
Pachenari et al. studied the effects of albendazole, a microtubule-targeted drug, on CCCs [28]. The authors reported the difference in grade I and grade IV CCCs, in terms of the proportion of microtubules and actin filaments. Micropipette aspiration was used to assess the viscoelastic behavior of grade I and IV of SW48 CCC line (more aggressive) compared to HT29 CCC line (less aggressive). Using relative fluorescence revealed that the ratio of actin filaments to microtubules in SW48 cells was equal to 1.33 ± 0.45, which was significantly lower than that of HT29 cells of 2.48 ± 0.85. The volume of the SW48 changes was significantly higher (about 3.5 times), after insertion of the cell body into the micropipette, when compared with HCT29 cells. SW48 cells have shown to be softer than the primary grade of CCCs, meaning that the decrease in cell elastic modulus was associated with their higher invasiveness. This property seemed to help the invasion of the cells through the microvasculature and cell spreading [28]. Extracellular vesicles (EVs) produced by the CRC cells must be a target, since according to Serrati et al. they contribute to the CRC dissemination into peritoneal cavities due to the EVs released, inducing the alteration of peritoneal mesothelial cells [29].
In terms of translation to the clinic, the AFM can be a promising tool in the surgery room, based on the concept that the CRC tissues are stiffer than healthy ones. In practice, after removing the tumor mass, the elasticity properties of tissues would be measured from the center to the periphery. When the stiffness values on the periphery of the tumor would be similar to the values of the healthy tissues around it, this would mean that it would not be necessary to extend the tumor area to be removed. Although this procedure is always carried out afterwards by anatomic pathology analysis, carrying out this analysis in situ would be faster and would avoid the eventual repetition of the surgery. A similar approach using Raman confocal microscopy has already been implemented in surgery of the head and neck in the Netherlands [30].
It was shown that, in CRC, using different approaches and techniques, bringing together biologists, physicists, biochemists, and medical specialists, is very important to deepen people's knowledge and to develop novel drugs and treatments for CRC.

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