Pregnancy Promotes Melanoma Metastasis through Enhanced Lymphangiogenesis

Abstract

The relationships of pregnancy and melanoma have been debatable. Our aim was to assess the influence of gestation on the course of melanoma in a classic murine model of tumor progression and in women. B16 mouse melanoma cells were injected in nonpregnant or pregnant mice on day 5 of gestation. Animals were evaluated for tumor progression, metastases, and survival. Tumor sections were analyzed for lymphatic and blood vessel number and relative surface and expression of angiogenic growth factors. Finally, primary melanomas from pregnant and nonpregnant women, matched for age and tumor thickness, were also considered. Tumor growth, metastasis, and mortality were increased in B16-injected pregnant mice. Tumors displayed an increase in intratumoral lymphangiogenesis during gestation. This increased lymphatic angiogenesis was not observed in normal skin during gestation, showing its specificity to the tumor. An analysis of melanoma from pregnant and matched nonpregnant women showed a similar increase in lymphatic vessels. Tumors from pregnant mice had increased expression of vascular endothelial growth factor A at the RNA and protein levels. The increased vascular endothelial growth factor A production by melanoma cells could be reproduced in culture using pregnant mouse serum. In conclusion, pregnancy results in increased lymphangiogenesis and subsequent metastasis. Caution should be applied in the management of patients with advanced-stage melanoma during gestation.

Adrenomedullin in lymphangiogenesis: from development to disease

“…Consistent with the finding that AM promotes tumor progression, several studies report increased lymphangiogenesis and metastasis in pregnant women with melanoma when compared with non-pregnant melanoma patients [94,95]. The direct cause of the increased lymphangiogenesis remains unknown.…”

Kaposi's Sarcoma and Pregnancy: Case Report and Literature Review

“…It has also been demonstrated that pregnancy promotes melanoma tumor growth via an increase in angiogenic and lymphangiogenic factors during the second and third trimesters [25,26]. Since angiogenesis appears to be an important feature of KS [27], the rise of these factors, especially vascular endothelial growth factors, could also play a major role in the recurrence and worsening of KS lesions during the second half of pregnancy.…”

Prognostic Factors in Cutaneous Melanoma

“…Investigators have consequently resorted to experimental systems. In a murine model in which B16 melanoma cells were injected into recipient pregnant and nonpregnant control mice, for example, the pregnant state promoted tumor growth, metastasis, and mortality and correlated with an increase in intratumoral angiogenesis during gestation [ 149 ]. With respect to the epidemiological evidence, defi nitive conclusions as to the prognostic effects of pregnancy, if any, have historically been hampered by the small size of the datasets available for analysis and insuffi cient multivariate control for the effects of the major prognostic factors, especially Breslow thickness.…”