Extracellular Hsp90α Promotes Tumor Lymphangiogenesis and Lymph Node Metastasis in Breast Cancer

Abstract

Early detection and discovery of new therapeutic targets are urgently needed to improve the breast cancer treatment outcome. Here we conducted an official clinical trial with cross-validation to corroborate human plasma Hsp90α as a novel breast cancer biomarker. Importantly, similar results were noticed in detecting early-stage breast cancer patients. Additionally, levels of plasma Hsp90α in breast cancer patients were gradually elevated as their clinical stages of regional lymph nodes advanced. In orthotopic breast cancer mouse models, administrating with recombinant Hsp90α protein increased both the primary tumor lymphatic vessel density and sentinel lymph node metastasis by 2 and 10 times, respectively. What is more, Hsp90α neutralizing antibody treatment approximately reduced 70% of lymphatic vessel density and 90% of sentinel lymph node metastasis. In the in vitro study, we demonstrated the role of extracellular Hsp90α (eHsp90α) as a pro-lymphangiogenic factor, which significantly enhanced migration and tube formation abilities of lymphatic endothelial cells (LECs). Mechanistically, eHsp90α signaled to the AKT pathway through low-density lipoprotein receptor-related protein 1 (LRP1) to upregulate the expression and secretion of CXCL8 in the lymphangiogenic process. Collectively, this study proves that plasma Hsp90α serves as an auxiliary diagnosis biomarker and eHsp90α as a molecular mediator promoting lymphangiogenesis in breast cancer.

Radiofrequency Irradiation Mitigated UV-B-Induced Skin Pigmentation by Increasing Lymphangiogenesis

“…HSP90 upregulates ERK, which in turn downregulates tyrosinase [37,38]. Moreover, HSP90 induces lymphangiogenesis through AKT, which is a downstream target of VEGFR 3 [35].…”

“…The activation of AKT and ERK is essential for lymphangiogenesis mediated by VEGF-C or VEGF-D [34]. In fact, HSP90 production activates AKT, thus leading to lymphangiogenesis by promoting the migration and tube formation of LECs [35]. HSP90 is also involved in the upregulation of ERK through BRCA1-associated protein 2 (BRAP)/mitogen-activated protein/extracellular signal-regulated kinase (MEK) in melanomas [36].…”

The Lymphatic System in Breast Cancer: Anatomical and Molecular Approaches

“…Interestingly, they demonstrated that in patients these levels were gradually augmented as the dissemination of cancer cells to regional lymph nodes increased, suggesting a role in lymphatic metastasis for Hsp90α. Moreover, in the same article the authors showed that the administration of recombinant Hsp90α protein in orthotopic breast cancer mouse models enhanced the number of tumour lymphatic vessels and lymphatic metastases, which were blocked by a Hsp90α neutralizing antibody [99]. In vitro, Hsp90α revealed a potent pro-lymphangiogenic characteristic, increasing both the migration and the tube formation of lymphatic endothelium.…”

“…Recently, Hou and colleagues [99] conducted a large-scale clinical trial to investigate the plasma levels of Hsp90α as a biomarker for breast cancer. Interestingly, they demonstrated that in patients these levels were gradually augmented as the dissemination of cancer cells to regional lymph nodes increased, suggesting a role in lymphatic metastasis for Hsp90α.…”

Extracellular HSP90 Machineries Build Tumor Microenvironment and Boost Cancer Progression

“…Cells of the tumor microenvironment also express HSP90 receptors and several studies reported the binding of HSP90 to their surface ( Calderwood et al, 2016 ). eHSP90α may mediate fibroblast migration and conversion to cancer associated fibroblasts ( Bohonowych et al, 2014 ; Tang et al, 2019 ) as well as migration and tubulogenesis in lymphatic endothelial cells ( Hou et al, 2021 ). By interacting with immune cells in the tumor microenvironment, HSP90 may also exert anti-tumoral functions.…”