Lymph Circulating Tumor Cells Research Articles

Abstract C114: Lymph circulating tumor cells are phenotypically different from tumor cells circulating in the blood

Abstract Breast cancer is the most common cancer in women. However, metastasis is the leading cause of death. When the tumor cell migrates from the primary tumor, it can disseminate into the blood circulation or lymphatic system. It has been proven that 80% of malignant carcinoma choose the lymphatic system over the vascular system. Despite the importance of sentinel lymph node (SLN) metastasis as a staging marker, lymphatically disseminated tumor cells (LCTCs) in transit from the primary tumor to the SLN have never been captured, characterized and compared to blood-borne tumor cells (BCTCs) in the same host. Here we use a microsurgical technique to collect draining lymph in situ from a growing tumor prior to its entry in SLN in syngeneic animals and patients with breast cancer. Unlike BCTC, LCTCs are found in clusters that exhibit a hybrid epithelial-mesenchymal phenotype, display a cancer stem cell CD44hi, CD24hi, ALDHA1hi signature, grow as mammospheres and are highly tumorigenic. We also showed that the lymph is enriched in tumor-derived exosome proteins and EGF growth factor. Characterization of LCTCs vs. BCTCs and the compilation of tumor-derived factors en route to the SLN can provide insights into the metastatic process and has relevance to cancer immunotherapy. Citation Format: Odalys J. Torres-Luquis, Sulma I. Mohammed. Lymph circulating tumor cells are phenotypically different from tumor cells circulating in the blood [abstract]. In: Proceedings of the Eleventh AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2018 Nov 2-5; New Orleans, LA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl):Abstract nr C114.

Abstract 2019A: TLR3 facilitate breast cancer metastasis to lymph node

Abstract Tumor cells can only enter the lymphatic circulation at the interface between the invasive edge of the tumor and the adjacent host stroma that contains the lymphatic circulation. The existence of this distance barrier means that it would be unlikely for tumor cells to passively enter the lymph drainage. Instead, Toll-like receptors (TLRs) are important mediators for active migration and chemotaxis for tumor cells entry into the lymphatic drainage from the primary tumor. Here we use a microsurgical technique to collect lymph circulating tumor cells (LCTC) prior to its entry into sentinel lymph node in rat models and determine if the TLR expression induces the migration and tumor progression. In our results, we observed high levels of TLR3 expression in LCTC when cells were treated with Poly (I:C), a synthetic ligand for TLR3 induction. NFkB activation was also observed in LCTCs, after TLR3 activation this pathway can express genes involved in cancer progression. In addition, when looking at the expression of cytokines and chemokines factors present in the lymph or secreted by the tumor cells, CXCL10 had a high expression on induced TLR3 of LCTC and its ligand CXCR3 was also expressed in the lymph. CXCL10 is involved in chemotaxis, induction of apoptosis, and regulation of cell growth. The CXCL10/CXCR3 signaling mediates paracrine interactions between tumor and stromal cells that govern leukocyte trafficking and angiogenesis. Suppression of CXCR3 or receptors signaling limits metastasis suggesting CXCR3 contributes to the metastatic process. TLR3 Knockdown prevented tumor growth and metastasis in rat. Our data suggest that for breast cancer metastasis, TLR3 might play a role in active migration of tumor cells and tumor progression. Activation of TLRs in tumor cells can dampen the anti-tumor functions of infiltrating immune cells, altering the inflammatory response and promoting cancer progression. Citation Format: Odalys J. Torres-Luquis, Sulma Mohammed. TLR3 facilitate breast cancer metastasis to lymph node [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2019A.

Lymph-circulating tumor cells show distinct properties to blood-circulating tumor cells and are efficient metastatic precursors.

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.