|BODENSTINE, THOMAS - University Of Alabama|
|CAO, XUEMEI - University Of Alabama|
|COOK, LEAH - University Of Alabama|
|ISMAIL, AIMEN - University Of Alabama|
|POWERS, KENT - University Of Alabama|
|MASTRO, ANDREA - Pennsylvania State University|
|WELCH, DANNY - University Of Alabama|
Submitted to: Chinese Journal of Cancer
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 1/24/2011
Publication Date: 3/1/2011
Citation: Bodenstine, T.M., Beck, B.H., Cao, X., Cook, L.M., Ismail, A., Powers, K.J., Mastro, A.M., Welch, D.R. 2011. Pre-osteoblastic MC3T3-E1 promote breast cancer cell growth in bone in a murine xenograft model. Chinese Journal of Cancer. 30(3):189-196.
Interpretive Summary: In humans, breast cancer cells metastasize to bone more than any other site in the body. This results in severe consequences for breast cancer patients and complicates therapeutic strategies. Within the bone, breast cancer cells are capable of controlling the activities of multiple cell types, including osteoclasts (bone resorbing cells), leading to degradation of bone. Previous reports have demonstrated that breast cancer cells are also able to modulate the activities of osteoblasts (bone forming cells), but much less is known about breast cancer cell interactions with osteoblasts and has been under studied. Using an animal model of breast cancer bone metastasis, we show that increasing the population of osteoblasts at sites of bone metastasis significantly increases breast cancer proliferation. These results suggest an underappreciated role for osteoblasts in promotion of tumor growth during early stages of breast cancer metastasis within the bone. Additionally, we show that breast cancer cells are capable of altering the types of molecules secreted by osteoblasts, which may contribute to the induced proliferative effect we observed. Collectively, these experiments provide a novel example of breast cancer modulation of the bone microenvironment.
Technical Abstract: The bones are the most common sites of breast cancer metastasis. Upon arrival within the bone microenvironment, breast cancer cells coordinate the activities of stromal cells, resulting in an increase in osteoclast activity and bone matrix degradation. In late stages of bone metastasis, breast cancer cells induce apoptosis in osteoblasts, which further exacerbates bone loss. However, in early stages, breast cancer cells induce osteoblasts to secrete inflammatory cytokines purported to drive tumor progression. To more thoroughly evaluate the role of osteoblasts in early stages of breast cancer metastasis to the bones, we used green fluorescent protein'la beled human breast cancer cell lines MDA-MB-231 and MDA-MB-435, which both induce osteolysis after intra'fe moral injection in athymic mice, and the murine pre'os teoblastic cell line MC3T3-E1 to modulate osteoblast populations at the sites of breast cancer metastasis. Breast cancer cells were injected directly into the femur with or without equal numbers of MC3T3-E1 cells. Tumors grew significantly larger when co'in jected with breast cancer cells and MC3T3-E1 cells than injected with breast cancer cells alone. Osteolysis was induced in both groups, indicating that MC3T3-E1 cells did not block the ability of breast cancer cells to cause bone destruction. MC3T3-E1 cells promoted tumor growth out of the bone into the extraosseous stroma. These data suggest that breast cancer cells and osteoblasts communicate during early stages of bone metastasis and promote tumor growth.