Abstract
Our knowledge of the biology underlying the development of brain metastases (BM) from breast cancer has improved over the last decade due to large clinical epidemiological studies, animal models of metastasis, and the use of high-resolution gene expression profiling technologies. However, there are still major gaps in our understanding of the mechanisms utilized by breast cancer cells to colonize the brain microenvironment, thus our arsenal of therapies remains relatively nonspecific, and the prognosis for breast cancer patients with BM remains poor. Additional insights into these mechanisms are necessary to facilitate the development of new preventive and curative therapeutic regimens to block this fatal disease. This paper aims to provide a general overview for the readers of what has been achieved in this field of research and its translation into clinical practice to date and to highlight exciting new areas of research that promise to inform the development of new targeted therapies for BM.
Highlights
Metastasis, or metastatic disease, is the spread of cancer cells from one organ to a distant site via the blood or lymph
Analysis of large autopsy series has showed that lung, breast, melanoma, renal, and colon cancers are the most common primary tumours to metastasize to the brain [2, 3]
It is hypothesized that a complex combination of tumour cell intrinsic and extrinsic processes eventually culminates in the activation of dormant cancer stem cells (CSCs) proliferation at distant sites [8]
Summary
Metastasis, or metastatic disease, is the spread of cancer cells from one organ to a distant site via the blood or lymph. At least three categories of metastasis genes have been proposed to facilitate the multistep metastatic cascade (reviewed in [11]): (1) “initiation” genes that facilitate detachment (e.g., CDH2 (encodes N-Cadherin) and TWIST), extracellular matrix degradation (e.g., MMPs) or angiogenesis (e.g., VEGF); (2) “progression” genes (e.g., PTGS2 (encodes COX-2) and MMP-1) that regulate extravasation of circulating tumour cells and are involved in metastatic colonisation; (3) “virulence” genes (e.g., IL6 and TNFα), which promote survival in circulation, and/or provide a proliferative advantage in the distant microenvironment Apart from these metastasis-promoting genes, there is a well-distinguished class of metastasis “suppressor” genes that represses tumour cell dissemination without any effect on primary tumour growth, including KAI-1, BRSM1, and NME1 [11]. Future therapeutic development is likely to be based on features of the metastases themselves
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