Abstract
While being the rarest skin cancer, melanoma is also the deadliest. To further drug discovery and improve clinical translation, new human cell-based in vitro models are needed. Our work strives to mimic the melanoma microenvironment in vitro as an alternative to animal testing. We used the self-assembly method to produce a 3D human melanoma model exempt of exogenous biomaterial. This model is based on primary human skin cells and melanoma cell lines while including a key feature for tumor progression: blood and lymphatic capillaries. Major components of the tumor microenvironment such as capillaries, human extracellular matrix, a stratified epidermis (involucrin, filaggrin) and basement membrane (laminin 332) are recapitulated in vitro. We demonstrate the persistence of CD31+ blood and podoplanin+/LYVE-1+ lymphatic capillaries in the engineered tissue. Chronic treatment with vemurafenib was applied to the model and elicited a dose-dependent response on proliferation and apoptosis, making it a promising tool to test new compounds in a human-like environment.
Highlights
The incidence of melanoma is constantly rising in developed countries[1] due to factors such as sunlight exposure and the use of tanning beds[2]
Lymphatic endothelial cells (LEC) can be isolated from Human microvascular endothelial cells (HMVEC) and incorporated into 3D constructs[25,26,27,28,29]. These lymphatic endothelial cells (LEC) are able to assemble into lymphatic capillaries distinct from those formed by blood endothelial cells (BEC) in a collagen gel[8]
We incorporated human microvascular endothelial cells to recapitulate the formation of blood and lymphatic capillaries in the dermal compartment, and melanoma spheroids were added to the tissue
Summary
The incidence of melanoma is constantly rising in developed countries[1] due to factors such as sunlight exposure and the use of tanning beds[2]. Human microvascular endothelial cells (HMVEC) or human umbilical vein endothelial cells (HUVEC) can be incorporated in skin constructs, contributing to a more complex tumor microenvironment[17,18] Their ability to form a network of blood capillaries which are stable, functional and perfusable has been observed in different types of skin substitutes produced using cell sheets, collagen-chitosan sponges, decellularized dermis or hydrogels[8,10,14,19,20,21,22,23,24]. We incorporated human microvascular endothelial cells to recapitulate the formation of blood and lymphatic capillaries in the dermal compartment, and melanoma spheroids were added to the tissue We found that our model responded adequately to treatment regarding the proliferation and apoptosis of tumor cells, and by recapitulating changes of tumor morphology
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