The tumor microenvironment is abundant with exosomes that are secreted by the cancer cells themselves. Exosomes are nanosized, organelle-like membranous structures that are increasingly being recognized as major contributors in the progression of malignant neoplasms. A critical element in melanoma progression is its propensity to metastasize, but little is known about how melanoma cell-derived exosomes modulate the microenvironment to optimize conditions for tumor progression and metastasis. Here, we provide evidence that melanoma cell-derived exosomes promote phenotype switching in primary melanocytes through paracrine/autocrine signaling. We found that the mitogen-activated protein kinase (MAPK) signaling pathway was activated during the exosome-mediated epithelial-to-mesenchymal transition (EMT)-resembling process, which promotes metastasis. Let-7i, an miRNA modulator of EMT, was also involved in this process. We further defined two other miRNA modulators of EMT (miR-191 and let-7a) in serum exosomes for differentiating stage I melanoma patients from non-melanoma subjects. These results provide the first strong molecular evidence that melanoma cell-derived exosomes promote the EMT-resembling process in the tumor microenvironment. Thus, novel strategies targeting EMT and modulating the tumor microenvironment may emerge as important approaches for the treatment of metastatic melanoma.
To investigate the effects of total body irradiation on the healing of skin wounds, rats were irradiated with a (60)Co gamma-ray source, in which single doses ranged from 1 to 8 Gy. After irradiation, two whole-thickness circular skin wounds, 22 mm in diameter and covering 2.5% of the total body surface area, were made immediately on the back of each animal. The average healing time for the simple wound was 18.3 +/- 2.1 days, whereas when the wound was combined with 1, 2, 3, 4, 5, and 6 Gy of radiation, the average wound healing time was delayed by 0.3, 0.8, 1.1, 3.5, 6.2, and 9.5 days, respectively. The average healing time was significantly decreased with irradiation doses exceeding 4 Gy, as compared with the healing time for the simple wound without irradiation (p < 0.05). The statistical results showed that the percentage of the unclosed wound with the increased doses in combined radiation injury was significantly proportional to the recovery time kinetics.
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