A novel lymphatic pattern promotes metastasis of cervical cancer in a hypoxic tumour-associated macrophage-dependent manner
Open Access
- 23 January 2021
- journal article
- research article
- Published by Springer Science and Business Media LLC in Angiogenesis
- Vol. 24 (3), 549-565
- https://doi.org/10.1007/s10456-020-09766-2
Abstract
Lymphatic remodelling in the hypoxic tumour microenvironment (TME) is critically involved in the metastasis of cervical squamous cell carcinoma (CSCC); however, its underlying mechanisms remain unclear. Here, we uncovered a novel lymphatic pattern in the hypoxic TME, wherein lymphatic vessels (LVs) are encapsulated by tumour-associated macrophages (TAMs) to form an interconnected network. We describe these aggregates as LVEM (LVs encapsulated by TAMs) considering their advantageous metastatic capacity and active involvement in early lymph node metastasis (LNM). Mechanistic investigations revealed that interleukin-10 (IL-10) derived from hypoxic TAMs adjacent to LVs was a prerequisite for lymphangiogenesis and LVEM formation through its induction of Sp1 upregulation in lymphatic endothelial cells (LECs). Interestingly, Sp1high LECs promoted the transactivation of C–C motif chemokine ligand 1 (CCL1) to facilitate TAM and tumour cell recruitment, thereby forming a positive feedback loop to strengthen the LVEM formation. Knockdown of Sp1 or blockage of CCL1 abrogated LVEM and consequently attenuated LNM. Notably, CSCCnon-LNM is largely devoid of hypoxic TAMs and the resultant LVEM, which might explain its metastatic delay. These findings identify a novel and efficient metastasis-promoting lymphatic pattern in the hypoxic TME, which might provide new targets for anti-metastasis therapy and prognostic assessment.Keywords
Funding Information
- National Natural Science Foundation of China (81971341, 81672589)
- Natural Science Foundation of Guangdong Province (2017A030313872, 2018A030313804)
- Key scientific research platforms and research projects of universities in Guangdong Province (2018KQNCX204)
This publication has 57 references indexed in Scilit:
- High density of peritumoral lymphatic vessels measured by D2-40/podoplanin and LYVE-1 expression in gastric cancer patients: an excellent prognostic indicator or a false friend?Gastric Cancer, 2012
- The role of Sp1 and Sp3 in normal and cancer cell biologyAnnals of Anatomy - Anatomischer Anzeiger, 2010
- Improving Bioscience Research Reporting: The ARRIVE Guidelines for Reporting Animal ResearchPLoS Biology, 2010
- Soluble B and T Lymphocyte Attenuator Possesses Antitumor Effects and Facilitates Heat Shock Protein 70 Vaccine-Triggered Antitumor Immunity against a Murine TC-1 Cervical Cancer Model In VivoThe Journal of Immunology, 2009
- Tumor-Associated Macrophage-Induced Invasion and Angiogenesis of Human Basal Cell Carcinoma Cells by Cyclooxygenase-2 InductionJournal of Investigative Dermatology, 2009
- Expression of the hyaluronan receptor LYVE‐1 is not restricted to the lymphatic vasculature; LYVE‐1 is also expressed on embryonic blood vesselsDevelopmental Dynamics, 2008
- Organ selectivity in metastasis: regulation by chemokines and their receptorsClinical & Experimental Metastasis, 2007
- Sp transcription factor family and its role in cancerEuropean Journal of Cancer, 2005
- Macrophage migration and gene expression in response to tumor hypoxiaInternational Journal of Cancer, 2005
- Congenital MalformationsThe New England Journal of Medicine, 1983