The Role of Pregnancy-Induced Hormonal Milieu in Lymphoma Progression

Introduction: Lymphoma is the most common hematological cancer during pregnancy. Recent data suggest that pregnancy-associated lymphoma is characterized by an excessive involvement of reproductive organs, advanced disease stage at diagnosis and an aggressive course, potentially leading to a high death rate of mothers.

Objective: To determine the role of estrogen and progesterone in lymphoma progression.

Materials and Methods: Estrogen and progesterone receptors were evaluated by qPCR and flow-cytometry in human lymphoma cell lines (Raji and BL2) and lymph node stromal cells (HK). The hormones effect on Raji/BL2 proliferation was determined using trypan blue exclusion and CFSE dye, and their viability, either when cultured alone or in the presence of HK cells, was assessed by Annexin-V staining. Raji migratory capacity towards estrogen-treated HK cells conditioned medium was examined by Transwell^® inserts. In vivo, lymphoma progression and dissemination was compared in pregnant vs. non-pregnant balb/c mice, injected (SC or IV) with A20 mice lymphoma cells.

Results: Lymphoma and HK cells express estrogen and progesterone receptors. Estrogen-treated lymphoma cells demonstrated reduced proliferation and cell viability in a concentration dependent manner and progesterone further augmented this phenomenon when co-administered with estrogen. However, BL2 cells that were in direct contact with HK cells were protected from estrogen toxic effects. Interestingly, estrogen-containing conditioned medium inhibited Raji migration. In vivo, pregnant mice showed shorter overall survival and enhanced tumor growth.

Conclusion: Lymphoma cells express pregnancy-related hormone receptors. Indeed, estrogen induces cell death and reduces proliferation and migration. However, the in vivo studies, suggest a supportive effect of pregnancy on lymphoma progression. These contradicting results imply that other pregnancy-related factors affect the microenvironment to facilitate lymphoma progression. The underlying mechanisms should be studied.