Mechanisms of breast cancer metastasis

Abstract

Invasive breast cancer tends to metastasize to lymph nodes and systemic sites. The management of metastasis has evolved by focusing on controlling the growth of the disease in the breast/chest wall, and at metastatic sites, initially by surgery alone, then by a combination of surgery with radiation, and later by adding systemic treatments in the form of chemotherapy, hormone manipulation, targeted therapy, immunotherapy and other treatments aimed at inhibiting the proliferation of cancer cells. It would be valuable for us to know how breast cancer metastasizes; such knowledge would likely encourage the development of therapies that focus on mechanisms of metastasis and might even allow us to avoid toxic therapies that are currently used for this disease. For example, if we had a drug that targeted a gene that is critical for metastasis, we might even be able to cure a vast majority of patients with breast cancer. By bringing together scientists with expertise in molecular aspects of breast cancer metastasis, and those with expertise in the mechanical aspects of metastasis, this paper probes interesting aspects of the metastasis cascade, further enlightening us in our efforts to improve the outcome from breast cancer treatments.

Keywords: Breast cancer evolution; Cell clusters; Genes; Lymph node and systemic metastasis; Mitochondrial DNA.

Fig. 1

Evolutionary or phylogenetic trees provide a map of cancer development and progression. Cancer subclones are represented by different colored cells with distinct mutation combinations

Fig. 2

Clusters resist programmed cell death. Tumor cell clusters have increased survival at metastatic sites through several mechanisms including depletion of reactive oxygen species, resistance to NK cell killing, and pro-survival signals transduced downstream of cell–cell adhesion

Fig. 3

Tumor cell clusters contain intercellular nanolumina that concentrate signaling molecules. Left, transmission electron microscopy of an MMTV-PyMT tumor cell cluster. Between tumor cells we observe intercellular cavities lined by microvilli-like protrusions and sealed by cell–cell junctions. We find that the growth factor epigen is trafficked to and concentrated within nanolumina, resulting in cooperative pro-growth signaling during collective metastasis