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

Ginter Ginter,Entenberg Entenberg,Condeelis Condeelis,Oktay Oktay,Jones Jones,Karagiannis Karagiannis,Lin Lin

doi:10.3390/cancers11101507

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https://doi.org/10.3390/cancers11101507

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Abstract

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.

Highlights

In breast cancer, tumor cells may disseminate to lymph nodes and more distant organs, but the mechanism of dissemination and the subsequent risk of mortality resulting from these cells may not be the same
Since recent studies in animal models indicate that tumor cells can utilize the blood vasculature to further disseminate systemically from the lymph nodes [15,16], we examined if tumor microenvironment of metastasis (TMEM) doorways were present in metastatic foci in the lymph nodes and evaluated whether these doorways were
To examine the status of the lymphatic and blood vasculature in our breast cancer patient cohorts, we first evaluated the localization of blood vessel (BV) and lymphatic vessel (LV) in relation to benign breast stroma and benign breast glandular parenchyma (Figure 1A,B), and assessed the localization of BVs and LVs in relation to invasive tumor cell nests (TCNs) and the adjacent tumor-associated stroma (TAS) (Figure 1C–F)

Summary

Introduction

Tumor cells may disseminate to lymph nodes and more distant organs, but the mechanism of dissemination and the subsequent risk of mortality resulting from these cells may not be the same. The metastatic cascade most often begins with the detachment of single tumor cells from multicellular tumor cell nests following epithelial-to-mesenchymal transition (EMT) [5,6]. To disseminate hematogenously, these cells migrate towards intratumoral blood vessels and intravasate using specialized blood vessel doorways called the tumor microenvironment of metastasis (TMEM) [7]. While each component of TMEM is critical in the process of this hematogenous dissemination, it has been elucidated in prior clinical studies that the density of TMEM doorways in primary breast tumors is prognostic of distant metastasis, independently of lymph node status and other currently used prognosticators [10,11,12]

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