Abstract
Macrophages (MΦs) and reactive oxygen species (ROS) are implicated in carcinogenesis. The oxidative stress sensor, transient receptor potential ankyrin 1 (TRPA1), activated by ROS, appears to contribute to lung and breast cancer progression. Although TRPA1 expression has been reported in melanoma cell lines, and oxidative stress has been associated with melanocytic transformation, their role in melanoma remains poorly known. Here, we localized MΦs, the final end-product of oxidative stress, 4-hydroxynonenal (4-HNE), and TRPA1 in tissue samples of human common dermal melanocytic nevi, dysplastic nevi, and thin (pT1) and thick (pT4) cutaneous melanomas. The number (amount) of intratumoral and peritumoral M2 MΦs and 4-HNE staining progressively increased with tumor severity, while TRPA1 expression was similar in all samples. Hydrogen peroxide (H2O2) evoked a TRPA1-dependent calcium response in two distinct melanoma cell lines (SK-MEL-28 and WM266-4). Furthermore, H2O2 induced a TRPA1-dependent H2O2 release that was prevented by the TRPA1 antagonist, A967079, or Trpa1 gene silencing (siRNA). ROS release from infiltrating M2 MΦs may target TRPA1-expressing melanoma cells to amplify the oxidative stress signal that affects tumor cell survival and proliferation.
Highlights
Cutaneous melanoma is the most common and aggressive subtype of melanoma, arising from malignant transformation of epidermal melanocytes [1]
We observed that CD163+ve tumor associated MΦs (TAMs) were higher in thicker pT4 melanomas than those found in dermal nevi (Figure 1a–d)
While proinflammatory M1 MΦs are mainly involved in the initial phase of cancer development by creating a mutagenic microenvironment [52], in more advanced stages of cancer, TAMs often differentiate into anti-inflammatory M2 MΦs, which enhance tumor growth by creating an immunosuppressive tumor microenvironment (TME) by producing proangiogenic molecules and proteolytic enzymes to promote angiogenesis and tumor invasion [10]
Summary
Cutaneous melanoma is the most common and aggressive subtype of melanoma, arising from malignant transformation of epidermal melanocytes [1]. Macrophages (MΦs) and, tumor associated MΦs (TAMs) are implicated in all stages of melanogenesis, contributing to cancer progression and metastasis. MΦ increase in the tumor microenvironment (TME) negatively affects the prognosis of the patient with malignant melanoma [2,3,4,5]. The number of CD68+ve TAMs increases with increasing melanoma invasion and ulceration [13,14,15]. A dense intratumoral infiltration of both CD68+ve and CD163+ve TAMs has been reported in deeply-invasive malignant and metastatic melanomas compared to non-metastatic melanomas [16,17], and in malignant compared to benign melanocytic lesions [18]. MΦ total number is correlated with Breslow thickness, tumor stage, and poor prognosis [13,14,15,16,18]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
