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© 2000 HARCOURT PUBLISHERS LTD
THE CLINICAL PROBLEM
In West European women, breast cancer is the most
frequent cancer and the main cause of death due to
malignancy. In these patients bone metastases are
common and are associated with significant mor-
bidity (1–3). Bone pain is the major complication
occuring in 70% of the patients (4, 5). Pathological
fractures occur in about 20% and hypercalcemia in
about 15% of the patients (1, 6). Breast cancer
accounts for 30–50% of pathological fractures and
for 20–30% of the spinal cord compression episodes
in cancer. Bone metastases are predominantly of the
osteolytic type and are localized in the axial skeleton
especially in the spine, the ribs and pelvis (1, 6–9).
Patients with metastatic breast cancer cannot be
cured from their disease and their quality of life is
adversely affected by the frequency and severity of
the related morbidity. The mechanisms underlying
the apparent preference of breast cancer cells for the
skeleton are poorly understood. From the moment,
however, the cells are located in the bone micro-
environment they release factors which stimulate
bone resorption with a subsequent selective increase
in the attraction and growth of new cancer cells
to bone (Figure 1). Understanding the processes
involved in metastasis of cancer cells to bone and in
the destruction of its architecture could lead to
optimal management of metastatic bone disease.
THE METASTATIC PROCESS
Metastasis is the end result of a series of extremely
complicated processes which consist of many cell–cell
and cell–matrix interactions. The development of an
LABORATORY – CLINIC INTERFACE
Tumour progression and angiogenesis in bone
metastasis from breast cancer: new approaches to
an old problem
G. van der Pluijm, C. Löwik and S. Papapoulos
Leiden University Medical Center, Department of Endocrinology and Metabolic Diseases C4-86, 2333 ZA
Leiden,The Netherlands
Breast cancer metastasizes frequently to the skeleton and causes considerable morbidity and deterioration of the quality of
life.The clinical consequences of skeletal metastases are bone pain, pathological fractures, hypercalcaemia and nerve com-
pression syndromes. From the moment breast cancer cells are located in the bone microenvironment, they may release fac-
tors which stimulate bone resorption and angiogenesis leading to growth of skeletal metastases and a subsequent selective
increase in the attraction of new cancer cells to bone.
In this review, emerging new concepts of breast cancer–bone interactions, in particular the involvement of angiogenesis,
proteolysis and the role of cancer-induced bone resorption in skeletal metastasis are discussed. Better understanding
of the processes involved in the metastasis of cancer cells to bone, local tumour growth and subsequent destruction
of skeletal architecture can lead to optimal methods for the prevention and treatment of metastatic bone disease.
© 2000 Harcourt Publishers Ltd
Key words: Breast neoplasms; neoplasm metastasis; bone metastasis; metastatic bone disease; pathologic neovascularization;
angiogenesis; peptide peptidohydrolases; osteoclasts; cell surface receptors; extracellular matrix.
Address all correspondence to: Dr. Gabri van der Pluijm, Leiden
University Medical Center (LUMC), Department of
Endocrinology & Metabolic Diseases C4-R, Albinusdreef 2, 2333
ZA Leiden, the Netherlands.
CANCER TREATMENT REVIEWS 2000; 26: 11–27
doi: 10.1053/ctrv.1999.0143, available online at http://www.idealibrary.com on