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VEGFR1 activity modulates myeloid cell infiltration in growing lung metastases but is not required for spontaneous metastasis formation.

Dawson MR, Duda DG, Chae SS, Fukumura D, Jain RK - PLoS ONE (2009)

Bottom Line: Recent reports suggested that blocking VEGFR1 activity or the interaction with its ligands (VEGF and PlGF) has anti-tumor effects.All these effects may be exerted indirectly by recruitment of bone marrow-derived cells (BMDCs), such as myeloid cells.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.

View Article: PubMed Central - PubMed

Affiliation: Steele 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.

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Bone marrow-derived cell (BMDC) accumulation in the primary tumors, lung metastases and surrounding (peri-metastatic) lung tissues after VEGFR1 blockade.Confocal images of cryo-sectioned primary tumor (A–D), peri-metastatic lung tissue (E–H) and metastatic lung tumors (I–L) collected from BMT-Actb-GFP/C57BL mice (BMDCs are shown in green) after IgG (A, C, E, G, I, K) or MF1 (B, D, F, H, J, L) treatment. Tissues were counterstained with DAPI nuclear dye (in blue). The width of images in A–J is 512 µm and images in K and L are 256 µm across.
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pone-0006525-g004: Bone marrow-derived cell (BMDC) accumulation in the primary tumors, lung metastases and surrounding (peri-metastatic) lung tissues after VEGFR1 blockade.Confocal images of cryo-sectioned primary tumor (A–D), peri-metastatic lung tissue (E–H) and metastatic lung tumors (I–L) collected from BMT-Actb-GFP/C57BL mice (BMDCs are shown in green) after IgG (A, C, E, G, I, K) or MF1 (B, D, F, H, J, L) treatment. Tissues were counterstained with DAPI nuclear dye (in blue). The width of images in A–J is 512 µm and images in K and L are 256 µm across.

Mentions: To establish with precision the BMDCs infiltration after VEGFR1 blockade, we quantified the BMDCs in LLC1 and B16 tumors implanted in BMT-Actb-GFP/C57BL mice after treatment with MF1 at the time of resection (approximately 2 weeks after implantation). Antibody blockade of VEGFR1 – from the time of implantation – did not change the number of GFP+ BMDCs in primary LLC1 or B16 tumors (Figure 4A–B) [17]. However, when most mice spontaneously developed macroscopic metastases (2 weeks after primary tumor resection), we detected a significant increase in BMDC accumulation inside the LLC1 metastatic nodules and in the peri-tumor lung tissue, but not in B16 metastases (Figures 2 and 4E,L). Thus, the reduction by VEGFR1 blockade in BMDC accumulation in metastases is tumor dependent. However, prior to the time-point used by us for resection (days 14–16), BMDC “pre-metastatic niches” [10], and metastatic foci [13] should have been formed in the lungs in these tumor models. Thus, we measured the accumulation of BMDCs in the lungs at the earlier time points (i.e., days 0 and 10 after resection).


VEGFR1 activity modulates myeloid cell infiltration in growing lung metastases but is not required for spontaneous metastasis formation.

Dawson MR, Duda DG, Chae SS, Fukumura D, Jain RK - PLoS ONE (2009)

Bone marrow-derived cell (BMDC) accumulation in the primary tumors, lung metastases and surrounding (peri-metastatic) lung tissues after VEGFR1 blockade.Confocal images of cryo-sectioned primary tumor (A–D), peri-metastatic lung tissue (E–H) and metastatic lung tumors (I–L) collected from BMT-Actb-GFP/C57BL mice (BMDCs are shown in green) after IgG (A, C, E, G, I, K) or MF1 (B, D, F, H, J, L) treatment. Tissues were counterstained with DAPI nuclear dye (in blue). The width of images in A–J is 512 µm and images in K and L are 256 µm across.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2744279&req=5

pone-0006525-g004: Bone marrow-derived cell (BMDC) accumulation in the primary tumors, lung metastases and surrounding (peri-metastatic) lung tissues after VEGFR1 blockade.Confocal images of cryo-sectioned primary tumor (A–D), peri-metastatic lung tissue (E–H) and metastatic lung tumors (I–L) collected from BMT-Actb-GFP/C57BL mice (BMDCs are shown in green) after IgG (A, C, E, G, I, K) or MF1 (B, D, F, H, J, L) treatment. Tissues were counterstained with DAPI nuclear dye (in blue). The width of images in A–J is 512 µm and images in K and L are 256 µm across.
Mentions: To establish with precision the BMDCs infiltration after VEGFR1 blockade, we quantified the BMDCs in LLC1 and B16 tumors implanted in BMT-Actb-GFP/C57BL mice after treatment with MF1 at the time of resection (approximately 2 weeks after implantation). Antibody blockade of VEGFR1 – from the time of implantation – did not change the number of GFP+ BMDCs in primary LLC1 or B16 tumors (Figure 4A–B) [17]. However, when most mice spontaneously developed macroscopic metastases (2 weeks after primary tumor resection), we detected a significant increase in BMDC accumulation inside the LLC1 metastatic nodules and in the peri-tumor lung tissue, but not in B16 metastases (Figures 2 and 4E,L). Thus, the reduction by VEGFR1 blockade in BMDC accumulation in metastases is tumor dependent. However, prior to the time-point used by us for resection (days 14–16), BMDC “pre-metastatic niches” [10], and metastatic foci [13] should have been formed in the lungs in these tumor models. Thus, we measured the accumulation of BMDCs in the lungs at the earlier time points (i.e., days 0 and 10 after resection).

Bottom Line: Recent reports suggested that blocking VEGFR1 activity or the interaction with its ligands (VEGF and PlGF) has anti-tumor effects.All these effects may be exerted indirectly by recruitment of bone marrow-derived cells (BMDCs), such as myeloid cells.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.

View Article: PubMed Central - PubMed

Affiliation: Steele 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.

Show MeSH
Related in: MedlinePlus