Angiogenesis-mediated progression of micrometastasis to lethal macrometastasis is the major cause of death in cancer patients. Here, using mouse models of pulmonary metastasis, we identify bone marrow (BM)-derived endothelial progenitor cells (EPCs) as critical regulators of this angiogenic switch. We show that tumors induce expression of the transcription factor Id1 in the EPCs and that suppression of Id1 after metastatic colonization blocked EPC mobilization, caused angiogenesis inhibition, impaired pulmonary macrometastases, and increased survival of tumor-bearing animals. These findings establish the role of EPCs in metastatic progression in preclinical models and suggest that selective targeting of EPCs may merit investigation as a therapy for cancer patients with lung metastases.

Glioblastoma multiforme is the most common highly aggressive human brain cancer, and receptor tyrosine kinases have been implicated in the progression of this malignancy. We have recently identified anaplastic lymphoma kinase (ALK) as a tyrosine kinase receptor for pleiotrophin, a secreted growth factor that is highly expressed during embryonic brain development and in tumors of the central nervous system. Here we report on the contribution of pleiotrophin-ALK signaling to glioblastoma growth. We found ALK overexpressed in human glioblastoma relative to normal brain and detected ALK mRNA in glioblastoma cell lines. We reduced the endogenous ALK in glioblastoma cells by ribozyme targeting and demonstrated that this prevents pleiotrophin-stimulated phosphorylation of the anti-apoptotic protein Akt. Furthermore, this depletion of ALK reduced tumor growth of xenografts in athymic nude mice and prolonged survival of the animals because of increased apoptosis in the tumors. These findings directly implicate ALK signaling as a rate-limiting factor in the growth of glioblastoma multiforme and suggest potential utility of therapeutic targeting of ALK.

The progression of cancer to metastatic disease is a major cause of death. We identified miR-708 being transcriptionally repressed by polycomb repressor complex 2-induced H3K27 trimethylation in metastatic breast cancer. miR-708 targets the endoplasmic reticulum protein neuronatin to decrease intracellular calcium level, resulting in reduction of activation of ERK and FAK, decreased cell migration, and impaired metastases. Ectopic expression of neuronatin refractory to suppression by miR-708 rescued cell migration and metastasis defects. In patients with breast cancer, miR-708 expression was decreased in lymph node and distal metastases, suggesting a metastasis-suppressive role. Our findings uncover a mechanistic role for miR-708 in metastasis and provide a rationale for developing miR-708 as a therapeutic agent against metastatic breast cancer.

This study provides insight into the architecture of common genetic variation contributing to CRC etiology and improves risk prediction for individualized screening.

Fibroblast growth factor-binding protein (FGF-BP) 1 is a secreted protein that can bind fibroblast growth factors (FGFs) 1 and 2. These FGFs are typically stored on heparan sulfate proteoglycans in the extracellular matrix in an inactive form, and it has been proposed that FGF-BP1 functions as a chaperone molecule that can mobilize locally stored FGF and present the growth factor to its tyrosine kinase receptor. FGF-BP1 is upregulated in squamous cell, colon, and breast cancers and can act as an angiogenic switch during malignant progression of epithelial cells. For the present studies, we focused on FGF-1 and -2 and investigated interactions with recombinant human FGF-BP1 protein as well as effects on signal transduction, cell proliferation, and angiogenesis. We show that recombinant FGF-BP1 specifically binds FGF-2 and that this binding is inhibited by FGF-1, heparan sulfate, and heparinoids. Furthermore, FGF-BP1 enhances FGF-1-and FGF-2-dependent proliferation of NIH-3T3 fibroblasts and FGF-2-induced extracellular signal-regulated kinase 2 phosphorylation. Finally, in the chicken chorioallantoic membrane angiogenesis assay, FGF-BP1 synergizes with exogenously added FGF-2. We conclude that FGF-BP1 binds directly to FGF-1 and FGF-2 and positively modulates the biological activities of these growth factors. Fibroblast growth factors (FGFs)1 represent a family of over 20 distinct proteins that are widely expressed in various tissues. FGFs have been reported to be involved in both development and adult tissue homeostasis, as well as in angiogenesis and cancer progression. FGF-2 (basic FGF), a 16 -18-kDa protein, is one of the best-studied members of this family and has been shown to have a variety of biological effects in different cells and organ systems, including embryonic development, tumorigenesis, and angiogenesis (for a review, see Refs. 1 and 2).FGF-2 interacts with low affinity cell surface and extracellular matrix heparan sulfate proteoglycans, which enable the growth factor to bind and activate its high affinity tyrosine kinase receptors (FGFRs), thereby forming a trimolecular active complex (3-6). It has been reported that cell surface heparan sulfate proteoglycans can modulate the action of FGF-2 by increasing its affinity for FGFRs (7). Moreover, heparan sulfate proteoglycans seem to protect FGF-2 from degradation by proteases in the extracellular environment (8, 9) and modulate the bioavailability of FGF-2, generating a local reservoir for the growth factor (10). The binding of FGF-2 to the cell surface receptor induces receptor tyrosine kinase dimerization and autophosphorylation (11). The phosphorylated FGFRs associate and subsequently activate SH2 domain-containing downstream signaling molecules, such as phospholipase C␥ (12, 13) and Src (14,15). Moreover, upon ligand-dependent receptor autophosphorylation, adaptor proteins, such as Grb2 and Shc, link the FGFRs to the Ras/MAPK signaling cascade (16 -18). Grb2 and Shc form a complex with the GDP/GTP exchange factor Son of Sevenless (Sos), which ...

Emerging evidence indicates that bone marrow (BM)-derived endothelial progenitor cells (EPCs) contribute to angiogenesis-mediated growth of certain tumors in mice and human. EPCs regulate the angiogenic switch via paracrine secretion of proangiogeneic growth factors and by direct luminal incorporation into sprouting nascent vessels. While the contributions of EPCs to neovessel formation in spontaneous and transplanted tumors and to the metastatic transition have been reported to be relatively low, remarkably, specific EPC ablation in vivo has resulted in severe angiogenesis inhibition and impaired primary and metastatic tumor growth. The existence of a BM reservoir of EPCs, and the selective involvement of EPCs in neovascularization, have attracted considerable interest because these cells represent novel target for therapeutic intervention. In addition, EPCs are also being used as pharmacodynamic surrogate markers for monitoring cancer progression, as well as for optimizing efficacy of anti-angiogenic therapies in the clinic. This review will focus primarily on recent advances and emerging concepts in the field of EPC biology and discuss ongoing debates involving the role of EPCs in tumor neovascularization. For detailed information on the in vitro characterization of EPCs contribution to non-tumor pathologies, the reader is directed towards several excellent reviews and publications [1] [2] [3] [4–6] and reviews by Bertolini, Voest and Yoder in this issue.

Genetic susceptibility to colorectal cancer is caused by rare pathogenic mutations and common genetic variants that contribute to familial risk. Here we report the results of a two-stage association study with 18,299 cases of colorectal cancer and 19,656 controls, with follow-up of the most statistically significant genetic loci in 4,725 cases and 9,969 controls from two Asian consortia. We describe six new susceptibility loci reaching a genome-wide threshold of P<5.0E-08. These findings provide additional insight into the underlying biological mechanisms of colorectal cancer and demonstrate the scientific value of large consortia-based genetic epidemiology studies.

BACKGROUND: This study was undertaken to characterize the relation between the survival of patients with stage IIIB/IV nonsmall cell lung cancer (NSCLC) and pack-years of cigarette smoking (graded according to the American Joint Committee on Cancer staging system). METHODS: Data were analyzed from patients with stage IIIB/IV NSCLC who had completed a prospective smoking questionnaire. The impact of pack-years of cigarette smoking, age, sex, Karnofsky performance status (KPS), and the presence of weight loss >5% was evaluated on overall survival using univariate and multivariate analyses. RESULTS: Smoking history and clinical data were available for 2010 patients with stage IIIB/IV NSCLC (1004 women and 1006 men). Approximately 70% of patients (1409 patients) had smoked >15 pack-years, 13% (270) were former and current smokers who had smoked 15 pack-years, and 16% (331) were never-smokers (<100 lifetime cigarettes). Never-smokers had a longer median survival compared with former or current smokers (17.8 months vs 11.3 months; log-rank P < .001). Among smokers, patients with a 15 pack-year history of smoking had a longer median survival than patients who had smoked >15 pack-years (14.6 months vs 10.8 months; log-rank P ¼ .03). As the number of pack-years increased, the median overall survival decreased (log-rank P < .001). Multivariate analysis indicated that a history of smoking was an independent prognostic factor (hazard ratio, 1.36; P < .001). CONCLUSIONS: More cigarette smoking, measured in pack-years, was associated with decreased survival after a diagnosis of stage IIIB/IV NSCLC. Trials assessing survival in patients with stage IIIB/IV NSCLC should report a detailed cigarette smoking history for all patients.