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The role of CCL21 / CCR7 chemokine axis in breast cancer-induced lymphangiogenesis

Significance statement

Lymphatic metastasis is a frequent event in human breast cancer that can lead to metastasis in other organs, requiring early intervention. Lymphangiogenesis (generation of new lymphatic vessels) is often a precursor of lymphatic metastasis for most epithelial cancers. In the present study, the authors combine three different approaches to identify molecular regulators of lymphangiogenesis, their cellular sources and targets of actions. (1) They utilize in vitro studies with lymphatic endothelial cells (LEC) and human breast cancer cells to dissect the cellular and molecular partners in lymphangiogenesis. (2) They utilize a “directed in vivo lymphangionesis assay” with genetically manipulated human breast cancer cells grafted in nude mice to validate and extend their in vitro findings. (3) Finally, in situ studies are conducted in human breast cancer tissues to examine their clinical relevance. These studies unveil a novel mechanism in breast cancer-induced lymhangiogenesis and lymphatic invasion by human breast cancer cells. The authors show a bidirectional molecular cross-talk between the LEC and breast cancer cells via the CCR7/CCL21 and VEGF-R3/VEGF-C receptor/ligand pairs, that appear to promote lymphatic outgrowth and entry of breast cancer cells into the lymphatic vessels.  Activation of CCR7 expressed by breast cancer cells by its ligand CCL21 produced by the LEC or immune cells in the cancer micro-environment stimulates secretion of the lymphangiogenic factor VEGF-C by breast cancer cells via activation of PI3K/AkT pathway. In turn, tumor-derived VEGF-C, by activating VEGF-R3, promotes LEC proliferation, migration and capillary-like tube formation — the key cellular events in lymphangiogenesis. Furthermore, they discovered that newly formed LECs in mice also express CCR7, which when activated by CCL21 promotes lymphangiogenesis in situ. Finally they show that CCR7 is a novel marker for lymphangiogensis in human breast cancer in situ, strongly correlating with other known markers such as VEGF-C or podoplanin. Thus CCR7 appears to be a novel therapeutic target for blocking lymphatic metastasis.

 

The role of CCL21 CCR7 chemokine axis in breast cancer-induced lymphangiogenesis.  Global Medical Discovery

 

 

 

 

 

 

 

 

 

 

Journal Reference

Tutunea-Fatan E1, Majumder M2, Xin X3, Lala PK4,5,6. Mol Cancer. 2015;14(1):35.

Show Affiliations

1Department of Anatomy & Cell Biology, Schulich School of Medicine and Dentistry, Western University, 1151 Richmond St, London, ON, N6A 5C1, Canada. [email protected]

2Department of Anatomy & Cell Biology, Schulich School of Medicine and Dentistry, Western University, 1151 Richmond St, London, ON, N6A 5C1, Canada. [email protected]

3Department of Anatomy & Cell Biology, Schulich School of Medicine and Dentistry, Western University, 1151 Richmond St, London, ON, N6A 5C1, Canada. [email protected]

4Department of Anatomy & Cell Biology, Schulich School of Medicine and Dentistry, Western University, 1151 Richmond St, London, ON, N6A 5C1, Canada. [email protected]

5Department of Oncology, Schulich School of Medicine and Dentistry, Western University, 790 Commissioners Rd. E, London, ON, N6A 4L6, Canada. [email protected]

6Children’s Health Research Institute, 800 Commissioners Rd. E, London, ON, N6C 2V5, Canada. [email protected]

 

Abstract

BACKGROUND:

Tumor-induced lymphangiogenesis facilitates breast cancer progression by generating new lymphatic vessels that serve as conduits for tumor dissemination to lymph nodes and beyond. Given the recent evidence suggesting the implication of C-C chemokine ligand 21/chemokine receptor 7 (CCL21/CCR7) in lymph node metastasis, the aim of our study was to define the role of this chemokine pair in breast cancer-associated lymphangiogenesis.

METHODS:

The expression analysis of CCL21/CCR7 pair and lymphatic endothelial cell (LEC) markers inbreast cancer specimens was performed by means of quantitative real-time PCR. By utilizing CCR7 and CCL21 gene manipulated breast cancer cell implants into orthotopic sites of nude mice, lymphatic vessel formation was assessed through quantitative real-time PCR, immunohistochemistry and immunofluorescence assays. Finally, the lymphangiogenic potential of CCL21/CCR7 was assessed in vitro with primary LECs through separate functional assays, each attempting to mimic different stages of the lymphangiogenic process.

RESULTS:

We found that CCR7 mRNA expression in human breast cancer tissues positively correlates with the expression of lymphatic endothelial markers LYVE-1, podoplanin, Prox-1, and vascular endothelial growth factor-C (VEGF-C). We demonstrated that the expression of CCL21/CCR7 by breast cancer cells has the ability to promote tumor-induced lymph-vascular recruitment in vivo. In vitro, CCL21/CCR7 chemokine axis regulates the expression and secretion of lymphangiogenic factor VEGF-C and thereby promotes proliferation, migration, as well as tube formation of the primary human LECs. Finally, we showed that protein kinase B (AKT) signaling pathway is the intracellular mechanism of CCR7-mediated VEGF-C secretion by human breast cancer cells.

CONCLUSIONS:

These results reveal that CCR7 and VEGF-C display a significant cross talk and suggest a novel role of the CCL21/CCR7 chemokine axis in the promotion of breast cancer-induced lymphangiogenesis.

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