Estrogen induces lung metastasis through a host compartment-specific response.
Direct proliferative effects of estrogen (E(2)) on estrogen receptor-positive tumors are well documented; however, the potential for E(2) to mediate effects selective for the host (i.e., angiogenesis, vascular permeability, or stromal effects), which influence tumor growth and/or metastasis, has received less attention. In this study, we examine the capacity for E(2) to promote tumor growth and/or metastasis independent of direct effects on tumor cells. In these studies, we distinguish host versus tumor compartment components of E(2) action in tumor growth and metastasis by analysis of E(2)-nonresponsive tumor cells implanted in ovariectomized (OVX) mice that contain s.c. implants of placebo (OVX) or E(2)-containing slow-release pellets (OVX + E(2)). We show that the D121 lung carcinoma cell line is E(2)-nonresponsive, and following s.c. implantation in OVX versus OVX + E(2) mice, E(2) action on the host compartment leads to an increase in spontaneous metastasis but not primary tumor growth or neovascularization. Similarly, experimental lung metastasis of E(2)-nonresponsive 4T1 mammary carcinoma cells also leads to increased tumor burden in the lungs of OVX + E(2) mice. These results suggest that the E(2) status of the host compartment influences late steps in tumor cell metastasis that can provide important insights into the role of E(2) in the tumor versus host compartments.
Division of Cancer and Vascular Biology, La Jolla Institute for Molecular Medicine, 4570 Executive Drive, Ste. 100, San Diego, CA 92121, USA.
Carole L
CL
Banka
Caren V
CV
Lund
Mai T N
MT
Nguyen
Andrew J
AJ
Pakchoian
Barbara M
BM
Mueller
Brian P
BP
Eliceiri
D000818:Animals; D001943:Breast Neoplasms / Q000098:blood supply / Q000473:pathology*; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D004958:Estradiol / Q000633:toxicity*; D047628:Estrogen Receptor alpha / Q000096:biosynthesis; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000098:blood supply / Q000139:chemically induced / Q000473:pathology / Q000556:secondary*; D008325:Mammary Neoplasms, Experimental / Q000098:blood supply / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009376:Neoplasms, Hormone-Dependent / Q000098:blood supply / Q000139:chemically induced / Q000473:pathology / Q000556:secondary*; D009389:Neovascularization, Pathologic / Q000473:pathology
D047628:Estrogen Receptor alpha; D004958:Estradiol