Abstract
The leading cause of breast cancer‐associated death is metastasis. In 80% of solid tumors, metastasis via the lymphatic system precedes metastasis via the vascular system. However, the molecular properties of tumor cells as they exit the primary tumor into the afferent lymphatics en route to the sentinel lymph nodes (SLNs) are not yet known. Here, we developed an innovative technique that enables the collection of lymph and lymph‐circulating tumor cells (LCTCs) en route to the SLN in an immunocompetent animal model of breast cancer metastasis. We found that the gene and protein expression profiles of LCTCs and blood‐circulating tumor cells (BCTCs) as they exit the primary tumor are similar, but distinct from those of primary tumors and lymph node metastases (LNMs). LCTCs, but not BCTCs, exist in clusters, display a hybrid epithelial/mesenchymal phenotype and cancer stem cell‐like properties, and are efficient metastatic precursors. These results demonstrate that tumor cells that metastasize through the lymphatic system are different from those spread by blood circulation. Understanding the relative contribution of these cells to overall peripheral blood‐circulating tumor cells is important for cancer therapy. Whether these two types of cell occur in cancer patients remains to be determined.
Highlights
Breast cancer is the most common malignancy in women
We found that in contrast to blood-circulating tumor cells (BCTCs), lymph-circulating tumor cells (LCTCs) exist in clusters, display a hybrid epithelial/ mesenchymal (E/M) phenotype and cancer stem celllike properties, and constitute extraordinarily efficient metastatic precursors
This procedure is similar to the procedure that is routinely performed for sentinel lymph nodes (SLNs) dissection in women with breast cancer
Summary
Breast cancer is the most common malignancy in women. The leading cause of breast cancer-associated death is metastasis (Weigelt et al, 2005). Advances in early diagnosis and systemic adjuvant therapy targeting primary tumors have significantly improved survival in women with breast cancer, treatments for metastatic disease remain less effective. The problem in identifying therapies targeting metastatic disease is our incomplete understanding of tumor biology during the metastatic process. Tumor cells detach from the primary tumor and may intravasate into and disseminate through the blood circulation or lymphatic system; either route of dissemination can lead to the venous circulation, as the lymphatics drain into the blood (Wong and Hynes, 2006). In 80% of solid tumors, metastasis via the Abbreviations BCTCs, blood-circulating tumor cells; CTLs, CD8+ cytotoxic T lymphocytes; E/M, epithelial/mesenchymal; EMT, epithelial–mesenchymal transition; FACS, fluorescence-activated cell sorting; GRO KC, keratinocyte chemoattractant/human growth-regulated oncogene; IP-10, IFNc-induced protein 10; IPAD, immuno-paired-antibody detection; LCTCs, lymph-circulating tumor cells; LNMs, lymph node metastases; MHC, major histocompatibility complex; SD, standard deviation; SLNs, sentinel lymph nodes; TNF, tumor necrosis factor; VEGF, vascular endothelial growth factor
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