Lymph-Circulating Tumor Cells show distinct properties to Blood-Circulating Tumor Cells and constitute extraordinary efficient metastatic precursors

Abstract

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. We developed an innovative technique that enables the collection of lymph and lymph-circulating tumor cells (LCTCs) en route to the SLN in immunocompetent animal model of breast cancer metastasis. We found that LCTCs and blood circulating tumor cells (BCTCs) as exited the primary tumor shared similar gene and protein expression profiles that were distinct from those of primary tumors and lymph node metastases (LNMs) despite their common parental cell origin. LCTCs but not BCTC exist in clusters, display a hybrid epithelial/mesenchymal phenotype and cancer stem cell-like properties and constitute extraordinarily efficient metastatic precursors. These results demonstrate that tumor cell metastasizing through the lymphatic are different from those spread by the blood circulation. The contribution of these cells to overall peripheral blood CTC is important in cancer therapy. Whether these two types of cells occur in cancer patients remain to be determined.\n\nStatement of significanceThe presence of tumor cells in the SLN denotes poor prognosis and worse patient outcomes. We have developed a capability to routinely collect these tumor cells before they reach their first stop, SLN, in their metastatic journey to distant sites. Examination of these cells and their lymph microenvironment revealed that they are molecularly different from their tumor of origin, their LNMs and their counterpart cells in the blood. This is the first time these cells are captured and studied. The approach will provide a new level of information that is highly relevant to our understanding of metastasis.