Radiotherapy-induced decreases in substance P levels may potentiate melanoma growth

Abstract

Abstract. Substance P, a member of the tachykinin family, is expressed in primary invasive malignant melanomas, metastatic melanomas, melanomas in situ, atypical naevi, and spindle and epithelioid cell naevi. The role of substance P in cancer development and progression is not clear. Radiotherapy, which is used extensively in the treatment of malignancies, alters substance P levels. It is, however, not known whether radiotherapy affects substance P levels in melanomas or in the tumor microenvironment. Given the fact that melanomas express substance P, possible radiation-induced changes in substance P content may underlie their radio-resistance. Hence, the aim of the present study was to determine the effects of radiotherapy on the growth of B16F10 melanomas as well as on the tumor and systemic expression of substance P. In vivo exposure of tumor-bearing C5BL/6 mice to ionizing radiation (45 Gy administered in three fractions) arrested tumor growth for three weeks and induced 3-fold increases in survival, as well as decreasing substance P levels in primary tumors and the surrounding skin. Although radiotherapy was applied locally (1 x 1 cm) at the mid-flank region of the animal, it also induced systemic changes in the levels of substance P. Specifically, radiotherapy decreased substance P levels in skin distant from the radiation field as well as in the lungs and adrenals. In order to understand the significance of this effect, B16F10 cells and cells made from metastatic lesions (B16LNAD cells) were treated with substance P. Substance P inhibited the growth of B16F10 and B16LNAD cells and further potentiated the inhibitory effects of radiotherapy. These findings demonstrate for the first time that substance P inhibits melanoma growth, and that radiotherapy-induced decreases in substance P levels may underlie the radio-resistance of melanomas.

Neuroendocrine Factors in Melanoma Pathogenesis

“…However, other studies have reported conflicting results regarding the effect of SP on melanoma. A study on B16F10 and B16LNAD melanoma cells has shown that SP inhibits tumor growth and potentiates the effects of radiotherapy [ 235 ].…”

Future of radiation therapy for malignant melanoma in an era of newer, more effective biological agents

“…A popular hypofractionated regimen involving a dose of 7 Gy per fraction delivered on days 1, 7, and 21 for postoperative patients demonstrated complete remission rates of 40%, with greater than 90% local control rates at four years 5. Some of the radioresistance based on recently reported in vivo biological data from mice suggests that a radiation-induced decrease in substance P may partly explain the radioresistant nature of some melanoma cell lines,10 and that altered fractionation regimens may be needed to overcome this based on clinical studies 5…”