VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche

Abstract

The cellular and molecular mechanisms by which a tumour cell undergoes metastasis to a predetermined location are largely unknown. Here we demonstrate that bone marrow-derived haematopoietic progenitor cells that express vascular endothelial growth factor receptor 1 (VEGFR1; also known as Flt1) home to tumour-specific pre-metastatic sites and form cellular clusters before the arrival of tumour cells. Preventing VEGFR1 function using antibodies or by the removal of VEGFR1(+) cells from the bone marrow of wild-type mice abrogates the formation of these pre-metastatic clusters and prevents tumour metastasis, whereas reconstitution with selected Id3 (inhibitor of differentiation 3)-competent VEGFR1+ cells establishes cluster formation and tumour metastasis in Id3 knockout mice. We also show that VEGFR1+ cells express VLA-4 (also known as integrin alpha4beta1), and that tumour-specific growth factors upregulate fibronectin--a VLA-4 ligand--in resident fibroblasts, providing a permissive niche for incoming tumour cells. Conditioned media obtained from distinct tumour types with unique patterns of metastatic spread redirected fibronectin expression and cluster formation, thereby transforming the metastatic profile. These findings demonstrate a requirement for VEGFR1+ haematopoietic progenitors in the regulation of metastasis, and suggest that expression patterns of fibronectin and VEGFR1+VLA-4+ clusters dictate organ-specific tumour spread.

The Multifaceted Roles Neutrophils Play in the Tumor Microenvironment

“…This theory was expanded upon when tumors were shown to directly enhance the seeding of circulating cells in the lungs [299], suggesting that the tumor can modulate the "soil" to make it more compatible with the "seed". Later studies have shown the direct involvement of bone marrow derived VEGFR1 + progenitor cells [300,301] in generating the pre-metastatic niche that is more receptive toward incoming tumor cells. These cells were identified as of myeloid lineage, and appeared not to differentiate, but maintained their expression of immature surface markers including c-Kit and Sca-1 within the tissue parenchyma [300].…”

“…Later studies have shown the direct involvement of bone marrow derived VEGFR1 + progenitor cells [300,301] in generating the pre-metastatic niche that is more receptive toward incoming tumor cells. These cells were identified as of myeloid lineage, and appeared not to differentiate, but maintained their expression of immature surface markers including c-Kit and Sca-1 within the tissue parenchyma [300]. Of note, the formation of the pre-metastatic niche was found to be organ specific.…”

Somatic stem cells and the origin of cancer

“…Furthermore, the molecular machinery used by normal stem cells for homing to or mobilizing from the niche may be utilized by cancer stem cells for invasion and metastasis 151 . Still, the idea of cancer as a consequence of stem cell niche mutations is hypothetical, although recent data support the role of the vascular niche in initiating metastasis 152 . In addition, skin tumors can be caused by telomerase activation, which promotes epidermal stem cell mobilization out of their niche together with increased cell proliferation 97,103 .…”

Potential of tumour cells for delivering oncolytic viruses

“…4 Furthermore, emerging evidence suggests that some primary tumour cells release soluble factors that induce a specific population of non-malignant haematopoietic cells to mobilize and settle in distant organ tissues, thereby establishing a 'pre-metastatic niche' that lays a foundation for incoming circulating cancer cells. 10 This raises the fascinating possibility that pre-selected autologous patient-derived tumour cells isolated from the patient's primary tumour might be used to target organs suspected of harbouring metastases, and to deliver antineoplastic products, including OVs, locally.…”

“…53 By administering such Trojan horses at the time of primary tumour resection, which often correlates with the release of metastatic growth from anti-angiogenic restrictions, 54 it should be possible to promote their infiltration into the pre-metastatic niche. 10 These frontline cells could be further armed with specific secreted or membrane-bound molecules providing an anchorage for subsequent homing of infected OV carriers or systemically applied viruses. This strategy is obviously not devoid of risk, as it should initially promote tumour feeding.…”