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.

Hallmarks of Bone Metastasis

“…The requirement to maintain bone homeostasis and protect (as much as possible) bone mass and strength, in the face of oncologic treatments that kill tumor cells, is fundamental. Recent studies have described significant negative effects of standard chemotherapeutic agents on bone healing, suggesting that the specific treatments (or the tumor cells themselves) may have altered the behavior and/or differentiated activity of osteoclasts, osteoblasts, and/or osteocytes [106–108]. …”

New therapeutic targets for cancer bone metastasis

“…By comparing peripheral blood plasma in patients with breast cancer bone metastases to healthy volunteers, Martinez and colleagues found that the plasma from patients can induce trans-endothelial migration of MCF-7 cells (a human breast adenocarcinoma cell line). These findings indicate that there are circulating factors in these patients that may promote intravasation, angiogenesis, survival and EMT of circulating tumor cells [40]. …”

Involvement of macrophage migration inhibitory factor and its receptor (CD74) in human breast cancer

“…Currently, there is a general consensus that MIF promotes tumor growth by several mechanisms; it stimulates cancer cell proliferation by triggering the MAPK/PI3K/Akt pathways, inhibits induction of p53-dependent apoptosis, increases production of vascular endothelial growth factor (VEGF) and inhibits the antitumor immune response (4–6). Moreover, it modulates metastatic behavior of tumor cells and affects tumor stromal cells (7,8). On the cellular level, MIF is stored in the cytoplasmic compartment and is released in response to several stimuli.…”