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Open AccessArticle

Tumor Microenvironment of Metastasis (TMEM) Doorways Are Restricted to the Blood Vessel Endothelium in Both Primary Breast Cancers and Their Lymph Node Metastases

1
Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY 10065, USA
2
Department of Anatomy and Structural Biology, Einstein College of Medicine/Montefiore Medical Center, Bronx, NY 10461, USA
3
Gruss-Lipper Biophotonics Center, Einstein College of Medicine/Montefiore Medical Center, Bronx, NY 10461, USA
4
Integrated Imaging Program, Einstein College of Medicine/Montefiore Medical Center, Bronx, NY 10461, USA
5
Department of Surgery, Einstein College of Medicine/Montefiore Medical Center, Bronx, NY 10461, USA
6
Department of Pathology, Einstein College of Medicine/Montefiore Medical Center, Bronx, NY 10461, USA
7
Department of Epidemiology and Population Health, Einstein College of Medicine/Montefiore Medical Center, Bronx, NY 10461, USA
*
Authors to whom correspondence should be addressed.
Cancers 2019, 11(10), 1507; https://doi.org/10.3390/cancers11101507
Received: 12 September 2019 / Revised: 30 September 2019 / Accepted: 2 October 2019 / Published: 8 October 2019
(This article belongs to the Special Issue Cancer Invasion and Metastasis)
Cancer cells metastasize from primary tumors to regional lymph nodes and distant sites via the lymphatic and blood vascular systems, respectively. Our prior work has demonstrated that in primary breast tumors, cancer cells utilize a three-cell complex (known as tumor microenvironment of metastasis, or TMEM) composed of a perivascular macrophage, a tumor cell expressing high levels of the actin-regulatory protein mammalian enabled (Mena), and an endothelial cell as functional “doorways” for hematogenous dissemination. Here, we studied a well-annotated case–control cohort of human invasive ductal carcinoma of the breast and metastatic lymph nodes from a separate breast cancer cohort. We demonstrate that in primary breast tumors, blood vessels are always present within tumor cell nests (TCNs) and tumor-associated stroma (TAS), while lymphatic vessels are only occasionally present in TCN and TAS. Furthermore, TMEM doorways not only exist in primary tumors as previously reported but also in lymph node metastases. In addition, we show that TMEM intravasation doorways are restricted to the blood vascular endothelium in both primary tumors and lymph node metastases, suggesting that breast cancer dissemination to distant sites from both primary tumors and metastatic foci in lymph nodes occurs hematogenously at TMEM doorways. TMEMs are very rarely detected at lymphatic vessels and do not confer clinical prognostic significance, indicating they are not participants in TMEM-associated hematogenous dissemination. These findings are consistent with recent observations that hematogenous dissemination from lymph nodes occurs via blood vessels. View Full-Text
Keywords: breast cancer; lymphatic vessel; lymph node; blood vessel; tumor microenvironment of metastasis (TMEM) breast cancer; lymphatic vessel; lymph node; blood vessel; tumor microenvironment of metastasis (TMEM)
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Ginter, P.S.; Karagiannis, G.S.; Entenberg, D.; Lin, Y.; Condeelis, J.; Jones, J.G.; Oktay, M.H. Tumor Microenvironment of Metastasis (TMEM) Doorways Are Restricted to the Blood Vessel Endothelium in Both Primary Breast Cancers and Their Lymph Node Metastases. Cancers 2019, 11, 1507.

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