Mechanical Properties of Growing Melanocytic Nevi and the Progression to Melanoma

et al. (2014) Mechanical Properties of Growing Melanocytic Nevi and the Progression to Melanoma. PLoS ONE 9(4): e94229. doi:10.1371/journal.pone.0094229 Mechanical Properties of Growing Melanocytic Nevi and the Progression to Melanoma Alessandro Taloni 0 1 Alexander A. Alemi 0 1 Emilio Ciusani 0 1 James P. Sethna 0 1 Stefano Zapperi 0 1 Caterina A. M. La Porta 0 1 Christof Markus Aegerter, University of Zurich, Switzerland 0 Funding: CAMLP, JPS and SZ acknowledge the hospitality of the Aspen Center for Physics, which is supported by the National Science Foundation, Grant PHY- 1066293. AA is supported by NSF-PHY-0941095; JSP by NCI U54CA143876; AT and SZ by the European Research Council AdG-2011 SIZEFFECTS; CAMLP by MIUR PRIN2010. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript 1 1 Istituto per l'Energetica e le Interfasi, Consiglio Nazionale delle Ricerche , Milan , Italy , 2 Laboratory of Atomic and Solid State Physics, Department of Physics, Cornell University , Ithaca , New York, United States of America , 3 Istituto Neurologico Carlo Besta, Milan , Italy , 4 Institute for Scientific Interchange Foundation , Turin , Italy , 5 Department of Biosciences, University of Milan , Milan , Italy Melanocytic nevi are benign proliferations that sometimes turn into malignant melanoma in a way that is still unclear from the biochemical and genetic point of view. Diagnostic and prognostic tools are then mostly based on dermoscopic examination and morphological analysis of histological tissues. To investigate the role of mechanics and geometry in the morpholgical dynamics of melanocytic nevi, we study a computation model for cell proliferation in a layered non-linear elastic tissue. Numerical simulations suggest that the morphology of the nevus is correlated to the initial location of the proliferating cell starting the growth process and to the mechanical properties of the tissue. Our results also support that melanocytes are subject to compressive stresses that fluctuate widely in the nevus and depend on the growth stage. Numerical simulations of cells in the epidermis releasing matrix metalloproteinases display an accelerated invasion of the dermis by destroying the basal membrane. Moreover, we suggest experimentally that osmotic stress and collagen inhibit growth in primary melanoma cells while the effect is much weaker in metastatic cells. Knowing that morphological features of nevi might also reflect geometry and mechanics rather than malignancy could be relevant for diagnostic purposes. - Melanocytic nevi are benign proliferations of melanocytes, the skin cells that produce the pigment melanin. They are by definition benign, but 50% of malignant melanomas arise from pre-existing nevi. Current diagnostic methods of melanocytic lesions are based on hystopathology and dermoscopy which reveal wide morphological diversity and evolution patterns whose origin is still unknown [1,2]. Leaving aside the controversial cases of Spitz and blue nevi, nevi are categorized from dermoscopic analysis into globular, reticular, structureless brown and mixed patterns (the latter are subdivided into mixed pattern with globular structureless areas in the center or mixed pattern with globuls at the periphery) [3]. The classical theory of nevi evolution formulated in 1893 by Unna [4] claims that nevi originate from melanocytes proliferating at the dermo-epidermal junction (lentigo simplex and junctional nevus) that form nests (compound nevus) and eventually migrate completely into the dermis (dermal nevus). More recently, Cramer described an opposite model known as the theory of upward migration [5]. Cramer suggested that precursor cells of melanocytes deriving from pluripotent stem cells of the neural crest wander during embryogenesis along nerves into the dermis, mature here and finally migrate as functional melanocytes into the epidermis. Cramers last migration step, however, was never broadly accepted. More recently Kittler et al. [6] suggest that nevi can migrate not only vertically but also horizontally, explaining how nevi can expand in the course of time. The underlying limitation of these theories is that they are based on hystopathological observation only, and do not reflect the dynamics of an individual nevus. From a diagnostic point of view it would be extremely useful to correlate the morphological features of nevi to the degree of malignancy or pre-malignancy. This issue is intricate because nevi proliferate in a complex microenvironment that can mediate cell behavior through the composition, structure, and dimensionality of the extracellular matrix (ECM), the polymeric scaffold that surrounds cells within tissues. For example, a malignant phenotype can be reverted into a nonmalignant one by specifically blocking aberrant adhesion of the cancer cell to its extracellular scaffold [7]. Recent research shows that mechanical properties of the tumor microenvironment and of the normal tissue can influence tumor growth and dynamics, in way that is still poorly understood [8 13]. Mechanical stresses such as those experienced by cancer cells during the expansion of the tumor against the stromal tissue have been shown to release and activate growth factors involved in the progression of cancer [14]. Moreover, the stiffness of the matrix surrounding a tumor determines how cancer cells polarize, adhere, contract, and migrate, and thus regulates their invasiveness [15]. Forces exerted by cancer cells as they migrate through the ECM has been quantified accurately using traction force microscopy [16,17] Another possibility is that mechanical stresses directly regulate the growth and death rates of cancer cells as shown by Montel et al. who induce osmotic stress by adding dextran, a biocompatible polymer that is not metabolized by cells [11,12]. Several studies in the literature indicate important changes in cellular functioning due to osmotic pressure [18,19], but the stresses involved (in the MPa range) were orders of magnitude larger than those (in the kPa range) studied in Refs. [11,12]. It is interesting to notice that compressive stresses of slightly less than 1 kPa applied through a piston were recently found to induce a metastatic phenotype in cancer cells [13]. While osmotic pressure may have a different origin than compressive mechanical pressure the effect on cells is exactly the same. This was demonstrated experimentally in Refs. [11,12] by applying osmotic pressure directly on the cells, by adding dextran to the growth medium, or indirectly, by placing the cells inside a dialysis bag which was then placed into a dextran solution. In both cases, the effect of pressure on the cells was found to be exactly the same. This is not surprising, since osmotic pressure corresponds indeed to a real mechanical pressure on the membrane due to the collisions with solute molecules. In a recent paper, Simonsen and coa (...truncated)