The chemokine stromal cell–derived factor (SDF-1; also known as chemokine ligand 12 [CXCL12]) regulates many essential biological processes, including cardiac and neuronal development, stem cell motility, neovascularization, angiogenesis, apoptosis, and tumorigenesis. It is generally believed that SDF-1 mediates these many disparate processes via a single cell surface receptor known as chemokine receptor 4 (CXCR4). This paper characterizes an alternate receptor, CXCR7, which binds with high affinity to SDF-1 and to a second chemokine, interferon-inducible T cell α chemoattractant (I-TAC; also known as CXCL11). Membrane-associated CXCR7 is expressed on many tumor cell lines, on activated endothelial cells, and on fetal liver cells, but on few other cell types. Unlike many other chemokine receptors, ligand activation of CXCR7 does not cause Ca2+ mobilization or cell migration. However, expression of CXCR7 provides cells with a growth and survival advantage and increased adhesion properties. Consistent with a role for CXCR7 in cell survival and adhesion, a specific, high affinity small molecule antagonist to CXCR7 impedes in vivo tumor growth in animal models, validating this new receptor as a target for development of novel cancer therapeutics.

Little is known about the formation of niches, local micro-environments required for stem cell maintenance. Here we develop an in vivo assay for adult hematopoietic stem cell (HSC) niche formation 1-2. With this assay, we identified a population of progenitor cells with surface markers CD45-Tie2-αV+CD105+Thy1.1- (CD105+Thy1-) that when sorted from 15.5 dpc fetal bones (fb) and transplanted under the adult mouse kidney capsule could recruit host-derived blood vessels, produce donor-derived ectopic bones through a cartilage intermediate, and generate a marrow cavity populated by host-derived long term reconstituting HSC (LT-HSC). In contrast, CD45-Tie2-αV+CD105+Thy1+ (CD105+Thy1+) fb progenitors form bone that does not contain a marrow cavity. Suppressing expression of factors involved in endochondral ossification, such as osterix and VEGF, inhibited niche generation 22-24. CD105+Thy1-progenitor populations derived from regions of the fetal mandible or calvaria that do not undergo endochondral ossification formed only bone without marrow in our assay27. Collectively, our data implicates endochondral ossification, bone formation that proceeds through a cartilage intermediate, as a requirement for adult HSC niche formation.

The receptor tyrosine kinase AXL is thought to play a role in metastasis, but the therapeutic efficacy of an AXL targeting agent remains largely untested in metastatic disease. In this study, we defined AXL as a therapeutic target for metastatic ovarian cancer. AXL is primarily expressed in metastases and advanced stage human ovarian tumors but not in normal ovarian epithelium. Genetic inhibition of AXL in human metastatic ovarian tumor cells is sufficient to prevent the initiation of metastatic disease in vivo. Mechanistically, inhibition of AXL signaling in animals with metastatic disease results in decreased invasion and MMP activity. Most importantly, soluble human AXL receptors that imposed a specific blockade of the GAS6/AXL pathway had a profound inhibitory effect on progression of established metastatic ovarian cancer without normal tissue toxicity. These results offer the first genetic validation of GAS6/AXL targeting as an effective strategy for inhibition of metastatic tumor progression in vivo. Furthermore, this study defines soluble AXL receptor therapy as a therapeutic candidate agent treating metastatic ovarian cancer, where current therapies are ineffective.