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Lipoxygenase mediates invasion of intrametastatic lymphatic vessels and propagates lymph node metastasis of human
Dontscho Kerjaschki1, Zsuzsanna Bago-Horvath, Margaretha Rudas
1Clinical Institute of Pathology, Medical University of Vienna, Vienna, Austria. dontscho.kerjaschki@meduniwien.ac.at
The Journal of Clinical Investigation
|May 5, 2011
Summary
Tumor cells invade lymphatic vessels and spread to lymph nodes through a process involving 15-lipoxygenase-1 (ALOX15). Inhibiting ALOX15 reduces mammary carcinoma metastasis, offering a potential therapeutic target for lymph node spread.
Area of Science:
- Oncology
- Molecular Biology
- Pathology
Background:
- Axillary lymph node metastasis is a key prognostic factor in mammary carcinoma.
- The mechanisms driving consecutive lymph node colonization remain poorly understood.
Purpose of the Study:
- To investigate the mechanisms of lymph node metastasis in mammary carcinoma.
- To identify molecular mediators of tumor cell invasion into lymphatic vessels.
Main Methods:
- Analysis of human mammary carcinomas and axillary lymph nodes.
- In vitro modeling of tumor bulk invasion using lymphatic endothelial monolayers.
- Pharmacological inhibition and shRNA knockdown of 15-lipoxygenase-1 (ALOX15).
- Xenograft tumor models and assessment of lymph node metastasis.
Main Results:
- Intrametastatic lymphatic vessels and tumor cell invasion correlate with postsentinel metastasis.
- Mammary carcinoma cells create defects in lymphatic endothelial cells via 12S-HETE, a metabolite of ALOX15.
- ALOX15 inhibition and knockdown reduce these defects and lymph node metastasis in vivo.
- ALOX15 expression in sentinel lymph node metastases inversely correlates with metastasis-free survival.
Conclusions:
- Lipoxygenase (specifically ALOX15) mediates tumor cell invasion into lymphatic vessels.
- ALOX15 plays a crucial role in the formation of lymph node metastasis in ductal mammary carcinomas.
- Targeting ALOX15 presents a potential strategy to inhibit mammary carcinoma spread.
