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Melanoma in the Eyes of Mechanobiology fcell-08-00054 February 11, 2020 Time: 16:43 # 1 REVIEW published: 11 February 2020 doi: 10.3389/fcell.2020.00054 Melanoma in the Eyes of Mechanobiology M. Manuela Brás1,2,3, Manfred Radmacher4*, Susana R. Sousa1,2,5 and Pedro L. Granja1,2,3† 1 Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal, 2 Instituto de Engenharia Biomédica, Universidade do Porto, Porto, Portugal, 3 Faculdade de Engenharia, Universidade do Porto, Porto, Portugal, 4 Institute for Biophysics, University of Bremen, Bremen, Germany, 5 Instituto Superior de Engenharia do Porto, Instituto Politécnico do Porto, Porto, Portugal Skin is the largest organ of the human body with several important functions that can be impaired by injury, genetic or chronic diseases. Among all skin diseases, melanoma is one of the most severe, which can lead to death, due to metastization. Mechanotransduction has a crucial role for motility, invasion, adhesion and metastization processes, since it deals with the response of cells to physical forces. Signaling Edited by: pathways are important to understand how physical cues produced or mediated Shamik Sen, by the Extracellular Matrix (ECM), affect healthy and tumor cells. During these Indian Institute of Technology Bombay, India processes, several molecules in the nucleus and cytoplasm are activated. Melanocytes, Reviewed by: keratinocytes, fibroblasts and the ECM, play a crucial role in melanoma formation. This Zhizhan Gu, manuscript will address the synergy among melanocytes, keratinocytes, fibroblasts cells Dana-Farber Cancer Institute, United States and the ECM considering their mechanical contribution and relevance in this disease. Takashi Kato, Mechanical properties of melanoma cells can also be influenced by pigmentation, Johns Hopkins University, which can be associated with changes in stiffness. Mechanical changes can be related United States with the adhesion, migration, or invasiveness potential of melanoma cells promoting a *Correspondence: Manfred Radmacher high metastization capacity of this cancer. Mechanosensing, mechanotransduction, and [email protected] mechanoresponse will be highlighted with respect to the motility, invasion, adhesion and †ORCID: metastization in melanoma cancer. Pedro L. Granja orcid.org/0000-0003-2761-4929 Keywords: melanoma, mechanobiology, melanocytes, keratinocytes, invasion, adhesion, migration, metastization Specialty section: This article was submitted to Cell Adhesion and Migration, MELANOMA a section of the journal Frontiers in Cell and Developmental Melanoma is one of the most severe skin cancers in humans with a mortality rate of 80% Biology (Hofschroer et al., 2017), due to the high resistance of this tumor to radiotherapy and chemotherapy Received: 15 July 2019 (Uong and Zon, 2010). The resistance to those treatments is due to high number of mutations Accepted: 21 January 2020 (approx. 75%) affecting specific genes, which lead to an increasing proliferation and survival (Kozar Published: 11 February 2020 et al., 2019). Immunotherapy is being exploited and investigated, and can be grouped in five types: Citation: (i) targeted antibodies (Sanlorenzo et al., 2014; Herzberg and Fisher, 2016); (ii) adoptive cell therapy Brás MM, Radmacher M, (Sanlorenzo et al., 2014); (iii) oncolytic virus therapy (Franklin et al., 2017); (iv) cancer vaccines Sousa SR and Granja PL (2020) Melanoma in the Eyes (Tuettenberg et al., 2007; Rodriguez-Cerdeira et al., 2017); and (v) immunomodulators (Johnson of Mechanobiology. et al., 2014; Faries, 2016; Cancer Research Institute, 2019). Chemotherapy and immunotherapy, Front. Cell Dev. Biol. 8:54. can be combined (biochemotherapy) regarding the stage disease (Sanlorenzo et al., 2014; Kozar doi: 10.3389/fcell.2020.00054 et al., 2019). The disease appears due to the malignant transformation of melanocytes located in Frontiers in Cell and Developmental Biology| www.frontiersin.org 1 February 2020| Volume 8| Article 54 fcell-08-00054 February 11, 2020 Time: 16:43 # 2 Brás et al. Melanoma in the Eyes of Mechanobiology the stratum basale of the epidermis although it is not clear primary melanoma is formed, it activates some signals, which how a melanocyte becomes malignant (Uong and Zon, 2010). will provide conditions that make the primary tumor strong such Bandarchi et al.(2010) suggested that a combination of up as: (i) attachment to the wall of the blood and/or lymphatic and down regulation of factors in several molecular pathways, vessels, enabling the movement through a new organ; (ii) enough seem to be the mechanism of transformation of normal into nutrients to grow; and (iii) it is resistant to the immune system. malignant melanocytes. If the disease is detected in an early With the three conditions mentioned before the primary tumor stage, there is a high probability of disease control, however, has the capacity to promote the metastization (At Melanoma when metastization occurs, the 5 years life expectancy drops Foundation, 2014). Why can melanoma develop in some body to 14%. Some epidemiological evidence related to melanoma parts that are not exposed to sunlight? It was suggested that there incidences in white and dark skinned population (Bandarchi are different changes occurring in genes of tissue cells exposed, et al., 2013) was presented by the authors whereas Bradford compared with the changes of genes of tissue cells not exposed (2009) presented epidemiological data about the total numbers to UV light. These mutations are transmitted into the next of melanoma incidences in the world. Dark skin results in a generations. Some genes appear during melanoma development, lower incidence of skin cancer due to the protection of the being not genetic. The transformation of melanocytes into increased epidermal melanin, which filters UV light twice as good melanoma cells is a very complex process, which involves several as white skin of Caucasian people (Bradford, 2009). Malignant signaling pathways reviewed by Paluncic et al.(2016). Briefly, melanoma are diagnosed by the ABCD rule, where A stands melanocytes are formed from their precursors: melanoblasts. for asymmetry, B for borders irregularity, C for color variation Melanoblasts differentiate into melanocytes, which get mature and D for diameter higher than 6 mm (Bandarchi et al., 2010). and start melanin production on melanosomes, which will be Melanoma shows three perceptible steps in tumor progression: transferred to keratinocytes. Melanomagenesis depends on the (i) one only affecting the epidermis; (ii) a second one affecting microenvironment, genetic and environmental factors. Although both the epidermis and the superficial papillary of the dermis; and genetic factors are crucial, they are not sufficient to induce (iii) a third one affecting the epidermis, dermis and hypodermis melanomagenesis (Paluncic et al., 2016). Melanoma tumors (vertical growth melanoma) (Bandarchi et al., 2010). Haass et al. are different from patient to patient. The environment, where (2005) divided the process of melanoma development in the melanoma tumors grow, is very complex depending on the following steps: (i) the damage of adhesion between keratinocytes interactions with ECM, microvasculature, fibroblastic cells and by down-regulation of E-cadherin, P-cadherin, desmoglein, and changing concentration of growth factor, cytokines, and nutrients connexins, which is influenced by growth factors produced by like glucose, oxygen, etc (Paluncic et al., 2016). Some signaling fibroblasts or keratinocytes; (ii) the interaction of melanoma pathways are more involved in tumor development, whereas with fibroblasts and/or melanoma with melanoma cells normally other signals are more crucial in the metastization process. not found in melanocytes, is up-regulated by MCAM and The description of biochemical pathways signaling is beyond N-cadherin; and (iii) alteration of integrin expression, inducing of this review, however the readers can find more information the loss of basement membrane anchorage (Haass et al., 2005). in different sources (Dissanayake et al., 2007; Straussman et al., According to the At Melanoma Foundation (AIM), melanoma 2012; Moriceau et al., 2015; Stark et al., 2015; Wang et al., 2016; develops in a similar way than other cancers: the DNA of a Ahmed and Haass, 2018; Kodet et al., 2018). Melanoma can be gene that controls cell division and proliferation is mutated. pigmented or not pigmented. The color of melanoma is due to This damaged gene results in a lack of control of cell division the existence of melanin, secreted and stored in melanosomes in and growth. This DNA mutation is passed to the daughter the cytoplasm of melanocytes. There are two types of melanin: cell during division. Melanoma is originated from a melanocyte eumelanin (has a black color) and pheomelanin (has a red/yellow that experienced too many mutations growing in an abnormal color). Normal melanocytes may or may not secret either type way. In the case of melanoma, this DNA mutation is caused of melanin (Lassalle et al., 2003). Mechanical properties and cell by an overexposure to UV radiation, affecting the melanocytes pigmentation are correlated (Sarna et al., 2013, 2014). (At Melanoma Foundation, 2014). When there is DNA damage, As melanoma needs a high amount of iron and copper, the several genes may be affected, resulting in encoding errors development of substances that target these ions could be another of several molecules hampering their function (At Melanoma methodology (Gorodetsky et al., 1986). Foundation, 2014;
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