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The Establishment of a Lung Colonization Assay for Circulating Tumor Cell Visualization in Lung Tissues
Published on: June 16, 2018
VEGFR1 activity modulates myeloid cell infiltration in growing lung metastases but is not required for spontaneous
Michelle R Dawson1, Dan G Duda, Sung-Suk Chae
1Steele Laboratory for Tumor Biology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Abstract:
The role of vascular endothelial growth factor receptor 1 (VEGFR1/Flt1) in tumor metastasis remains incompletely characterized. Recent reports suggested that blocking VEGFR1 activity or the interaction with its ligands (VEGF and PlGF) has anti-tumor effects. Moreover, several studies showed that VEGFR1 mediates tumor progression to distant metastasis. All these effects may be exerted indirectly by recruitment of bone marrow-derived cells (BMDCs), such as myeloid cells. We investigated the role of VEGFR1 activity in BMDCs during the pre-metastatic phase, i.e., prior to metastatic nodule formation in mice after surgical removal of the primary tumor. Using pharmacologic blockade or genetic deletion of the tyrosine kinase domain of VEGFR1, we demonstrate that VEGFR1 activity is not required for the infiltration of de novo myeloid BMDCs in the pre-metastatic lungs in two tumor models and in two mouse models. Moreover, in line with emerging clinical observations, we show that blockade of VEGFR1 activity neither prevents nor changes the rate of spontaneous metastasis formation after primary tumor removal. Prevention of metastasis will require further identification and exploration of cellular and molecular pathways that mediate the priming of the metastatic soil.
Insights
Vascular Endothelial Growth Factor Receptor 1 (VEGFR1) activity in bone marrow-derived cells is not required for myeloid cell infiltration during the pre-metastatic phase. Blocking VEGFR1 did not prevent or alter spontaneous metastasis formation in mice.
Area of Science:
- Oncology
- Immunology
- Cell Biology
Background:
- Vascular Endothelial Growth Factor Receptor 1 (VEGFR1/Flt1) is implicated in tumor metastasis, with some studies suggesting anti-tumor effects upon blockade.
- VEGFR1 may mediate tumor progression indirectly through the recruitment of bone marrow-derived cells (BMDCs), such as myeloid cells.
Purpose of the Study:
- To investigate the role of VEGFR1 activity within BMDCs during the pre-metastatic phase.
- To determine if VEGFR1 blockade affects myeloid cell infiltration or spontaneous metastasis formation.
Main Methods:
- Pharmacologic blockade and genetic deletion of the VEGFR1 tyrosine kinase domain in mouse models.
- Analysis of de novo myeloid BMDC infiltration into pre-metastatic lungs.
- Assessment of spontaneous metastasis formation after primary tumor removal.
Main Results:
- VEGFR1 activity in BMDCs is not essential for the infiltration of myeloid cells into pre-metastatic lungs.
- Blockade of VEGFR1 activity did not prevent or modify the rate of spontaneous metastasis formation.
- Findings align with clinical observations regarding VEGFR1 blockade and metastasis.
Conclusions:
- VEGFR1 activity within BMDCs does not play a critical role in the early stages of lung metastasis.
- Targeting VEGFR1 alone may not be sufficient for preventing tumor metastasis.
- Further research into alternative cellular and molecular pathways is needed to effectively prevent metastasis.
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