Bone marrow microenvironment and tumor progression

Abstract

The bone marrow constitutes an unique microenvironment for cancer cells in three specific aspects. First, the bone marrow actively recruits circulating tumor cells where they find a sanctuary rich in growth factors and cytokines that promote their proliferation and survival. When in the bone marrow, tumor cells profoundly affect the homeostasis of the bone and the balance between osteogenesis and osteolysis. As a consequence, growth and survival factors normally sequestered into the bone matrix are released, further fueling cancer progression. Second, tumor cells actively recruit bone marrow-derived precursor cells into their own microenvironment. When in the tumors, these bone marrow-derived cells contribute to an inflammatory reaction and to the formation of the tumor vasculature. Third, bone marrow-derived cells can home in distant organs, where they form niches that attract circulating tumor cells. Our understanding of the contribution of the bone marrow microenvironment to cancer progression has therefore dramatically improved over the last few years. The importance of this new knowledge cannot be underestimated considering that the vast majority of cancer treatments such as cytotoxic and myeloablative chemotherapy, bone marrow transplantation and radiation therapy inflict a trauma to the bone marrow microenvironment. How such trauma affects the influence that the bone marrow microenvironment exerts on cancer is still poorly understood. In this article, the reciprocal relationship between the bone marrow microenvironment and tumor cells is reviewed, and its potential impact on cancer therapy is discussed.

Fig. 1

VEGFR-1 and 2 positive precursor cells are released from the bone marrow. HSC are retained in the endosteal niche by a combination of cell–cell (Tie-2/angio-1), cell-matrix (α4β1/osteopontin) and receptor–ligand (CXCR-4/SDF-1) interactions. The mobilization of these cells toward the vascular niche and their release in the peripheral blood is in part controlled by MMP-9 which (1) degrades SDF-1, (2) degrades osteopontin, (3) solubilizes cKit-L and (4) degrades the basement membrane

Fig. 2

The primary tumor actively recruits BMDC. Tumor cells release SDF-1, VEGF, PlGF, M-CSF and other cytokines that attract HSC and MSC from the bone marrow. In the tumor tissue, VEGFR-1 pos. cells give rise to CD45 pos. myelo-monocytic cells, macrophages and mast cells that contribute to an inflammatory reaction and to the formation of the perivasculature. By producing MMP-9 these cells further contribute to the solubilization of VEGF and other growth factors. VEGFR-2 pos. cells give rise to endothelial cells and contribute to the formation of a de novo vasculature. MSC are recruited by primary tumors and give rise to pericytes and contribute to the formation of distant metastasis by expressing CCL-5/RANTES that stimulates tumor cell migration

Fig. 3

Tumor cells are recruited by the bone marrow where they alter the osteoblasts and osteoclast balance. SDF-1, which is abundantly present in the bone marrow, attracts CXCR-4 expressing tumor cells. When in the bone marrow tumor cells interact with osteoblasts and osteoclast precursor cells through the production of PTHrP, RANKL and other osteoclast activating factors. Alternatively, tumor cells stimulate MSC to make IL-6. As a result, osteoclasts are activated. Tumor cells also inhibit osteoblast activity and new bone formation by blocking the Wnt pathway via the production of Dkk1. This leads to an increase in bone degradation and release of growth factors

Fig. 4

The bone marrow releases VEGFR-1 and 2 pos. precursor cells that promote the development of distant metastases. VEGFR-1 BMDC cells can colonize distant organs via adhesion to fibronectin forming pre-metastatic niches (1). These cells release SDF-1 that attracts CXCR-4 circulating tumor cells (2). When established in these pre-metastatic niches, tumor cells secrete VEGF, PlGF and other cytokines that attract VEGFR-2 pos. BMDC that will contribute to neo-angiogenesis (3)

Fig. 5

Revisiting the administration of high dose chemotherapy. a Recent observations suggest that there is an increase in the level of EPC after pulse high dose chemotherapy. This increase may favor tumor progression and the establishment of distant metastases if these cells are recruited by the primary tumor and by pre-metastatic niches. b The administration of agents blocking the recruitment of VEGFR-1 and 2 positive BMDC between courses of high dose chemotherapy may prevent a stimulation of neo-angiogenesis and the formation of pre-metastatic niche post chemotherapy