title: Changes in the peripheral blood and bone marrow from untreated advanced breast cancer patients that are associated with the establishment of bone metastases.
abstract: Bone metastasis is an incurable complication of breast cancer affecting 70-80 % of advanced patients. It is a multistep process that includes tumour cell mobilisation, intravasation, survival in the circulation, extravasation, migration and proliferation in the bone marrow/bone. Although novel findings demonstrate the bone marrow microenvironment significance in bone metastatic progression, a majority of studies have focused on end-stage disease and little is known about how the pre-metastatic niche arises in the bone marrow/bone tissues. We demonstrated a significant increase in patients' peripheral blood plasma ability to induce transendothelial migration of MCF-7 cells compared with healthy volunteers. Moreover, high RANKL, MIF and OPG levels in patients' peripheral blood could play a role in the intravasation, angiogenesis, survival and epithelial-mesenchymal transition of circulating tumour cells. Also, we observed a significant increase in patients' bone marrow plasma capacity to induce transendothelial migration of MDA-MB231 and MCF-7 cells compared with healthy volunteers. Furthermore, patients' bone marrow mesenchymal stem cells could control the recruitment of tumour cells, modifying the MCF-7 and MDA-MB231 cell migration. In addition, we found a significantly higher MDA-MB231 cell proliferation when we used patients' bone marrow plasma compared with healthy volunteers. Interestingly, PDGF-AB, ICAM-1 and VCAM-1 levels in patients' bone marrow were significantly higher than the values of healthy volunteers, suggesting that they could be involved in the cancer cell extravasation, bone resorption and cancer cell proliferation. We believe that these results can reveal new information about what alterations happen in the bone marrow of advanced breast cancer patients before bone colonisation, changes that create optimal soil for the metastatic cascade progression.
authors.affiliation: Immunohematology Laboratory, Experimental Biology and Medicine Institute (IBYME), National Council of Scientific and Technical Research (CONICET), 2490 Vuelta de Obligado, 1428, Ciudad Autónoma de Buenos Aires, Buenos Aires, Argentina.
authors.forename: Leandro Marcelo
authors.initials: LM
authors.lastname: Martinez
authors.forename: Valeria Beatriz Fernández
authors.initials: VB
authors.lastname: Vallone
authors.forename: Vivian
authors.initials: V
authors.lastname: Labovsky
authors.forename: Hosoon
authors.initials: H
authors.lastname: Choi
authors.forename: Erica Leonor
authors.initials: EL
authors.lastname: Hofer
authors.forename: Leonardo
authors.initials: L
authors.lastname: Feldman
authors.forename: Raúl Horacio
authors.initials: RH
authors.lastname: Bordenave
authors.forename: Emilio
authors.initials: E
authors.lastname: Batagelj
authors.forename: Federico
authors.initials: F
authors.lastname: Dimase
authors.forename: Ana Rodriguez
authors.initials: AR
authors.lastname: Villafañe
authors.forename: Norma Alejandra
authors.initials: NA
authors.lastname: Chasseing
mesh_terms: D017209:Apoptosis; D001853:Bone Marrow / Q000473:pathology*; D001859:Bone Neoplasms / Q000097:blood / Q000556:secondary*; D001943:Breast Neoplasms / Q000097:blood / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D009362:Neoplasm Metastasis