Homing of Cancer Cells to the Bone

Abstract

A variety of tumor cells preferentially home to the bone. The homing of cancer cells to the bone represents a multi-step process that involves malignant progression of the tumor, invasion of the tumor through the extracellular matrix and the blood vessels and settling of the tumor cells in the bone. Gaining a greater understanding as to the mechanisms used by cancer cells in these processes will facilitate the design of drugs which could specifically target the homing process. In this review we will discuss the properties of tumor cells and the bone microenvironment which promote homing of a cancer cell to the bone. We will highlight the different steps and the molecular pathways involved when a cancer cell metastasize to the bone. Since bone is the major home for hematopoietic stem cells (HSCs), we will also highlight the similarities between the homing of cancer and HSC to the bone. Finally we will conclude with therapeutic and early detection strategies which can prevent homing of a cancer cell to the bone.

Pilot study of adoptive immunotherapy with sentinel node-derived T cells in muscle-invasive urinary bladder cancer

“…For a cancer cell to enter bone, multiple steps occur, including the expression of very late activation antigen-4 (VLA-4) and chemokine receptors such as CXCR4, CXCR6 and CXCR7 enabling binding to the endothelium. Following binding to the endothelium, cancer cells expressing appropriate chemokine receptors transmigrate in the direction of a chemokine gradient of stromal cellderived factor-1 (SDF-1) and CXCL16 produced by bone marrow cells [28]. Circulating T lymphocytes do not normally express CXCR4, CXCR6 and CXCR7 (O. Winqvist, unpublished observation), and therefore their entry into bone marrow is impeded.…”

Different molecular profiles are associated with breast cancer cell homing compared with colonisation of bone: evidence using a novel bone-seeking cell line

“…Bone-homing of breast cancer cells is most prominent in the highly vascular trabecular areas of the long bone metaphysis, where they lodge in a niche identical to, or largely overlapping with, the haematopoietic stem cell niche (Mishra et al 2011. It has been proposed that the mechanics of the sluggish sinusoidal vascular supply within the metaphysis give the haematopoietic precursors, as well as invading tumour cells, ample opportunity to move in and out of the marrow.…”

MRI for the detection of prostate cancer origin vertebral metastases in the preosteoblastic phase

“…Skeletal metastasis is preceded by a series of processes—the escape of metastatic cells from the primary prostate cancer into the blood stream, the establishment of marrow metastasis, proliferation within the marrow, promotion of osteoclastic and obsteoblastic activity leading to cortical bone invasion and overproduction of disorganised bone, which manifests radiologically/pathologically as the well-known ‘osteoblastic metastasis’ 4 7…”

“…Erstwhile hypothesis tried to explain this ‘unique bone-trophism’ to the increased rate of blood flow in the bone marrow, but such a hypothesis would ignore the fact that other sites, such as the pulmonary circulation is 30 times higher in magnitude compared with the bone marrow flow 9. Later it was suggested that the ‘slow flow’ that occurs in the bone marrow, along with the frequent change in direction in the vertebral Batson's valveless venous plexuses (the direction of flow dependent on the intrathoracic and intra-abdominal pressures) is a more feasible explanation for the ‘bone-trophism’ from prostate cancer 4 7…”

“…It has been discovered that prostate cancer cells express the chemokine receptor CXCR4 on their surface. This causes an affinity towards the bone microenvironment, which is rich in the chemokine named stromal-derived factor-1 (SDF-1) 4 7 10 11…”