Abstract
Unique characteristics in fetal development include scar-less wound healing and the paucity of tumor formation. Recent studies have demonstrated that the embryonic microenvironment can reverse melanoma cells to a benign melanocyte phenotype. We bioengineered embryonic-like compositions and tested the anti-cancer activity of this material on a panel of skin cancer lines. To simulate the embryonic environment, neonatal fibroblasts were grown in hypoxic suspension cultures. The cells reverted back into multipotent stem cells as evidenced by the upregulation of SOX2, Oct4, NANOG, and KLF4 genes, and by the expression of stem cell-associated proteins including Nodal, Brachyury, Nestin, and Oct4. Cell Conditioned Media (CCM) and human Extracellular Matrix Proteins (hECM) produced by these cells were tested for their ability to reduce cell viability in skin cancer cell lines. In vitro studies with CCM and hECM show reduction in Squamous Cell Carcinoma (SCC), Basal Cell Carcinoma (BCC) and melanoma cell number through upregulation of caspases and induction of apoptosis. In the chick allantoic membrane assay, melanoma load was reduced by up to 80% with hECM treatment compared to vehicle treated controls (p 0.05). Similar inhibition was seen with SCC cells. In a xenograft mouse model of subcutaneous melanoma, tumor growth was inhibited by 70% - 90%. These data suggest that CCM and hECM have anti tumor potential and might offer a new treatment strategy in skin cancer.
Highlights
Research has elucidated key roles that the tumor extracellular matrix (ECM) plays in promoting tumor growth and metastasis, as well as the anti-tumor properties of the innate host ECM
We have studied the effect of human Extracellular Matrix Proteins (hECM) and Cell Conditioned Media (CCM) on the growth of basal cell carcinoma (BCC), squamous cell carcinoma (SCC) and melanoma cell lines using in vitro and in vivo models
Western blot analysis performed on the hECM confirmed the presence of decorin, which has been associated with growth suppression of mammary carcinoma cells [9]
Summary
Research has elucidated key roles that the tumor extracellular matrix (ECM) plays in promoting tumor growth and metastasis, as well as the anti-tumor properties of the innate host ECM. The ability of cancer cells to expand locally and develop regional as well as distant metastasis relies on their biomechanical properties and their microenvironment which consists of collagens, laminins, a variety of growth factors and several matrix proteins [1]. Metastatic melanoma cells, when placed within the neural crest of the developing chicken egg, integrate and differentiate toward the resident cells’ phenotype, displaying features of normal, benign tissue [2,3]. Further evidence of the ability of mesenchymal products to influence cell phenotype was shown with melanocytes and melanoma cells; when normal primary melanocytes were cultured in contact with ECM isolated from melanoma tumors they differentiated into melanoma cells. Melanoma cells cultured in fetal ECM reverted into benign melanocytes [7]
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