Tissue factor (TF) expression by tumor cells correlates with metastasis clinically and supports metastasis in experimental settings. However, the precise pathways coupling TF to malignancy remain incompletely defined. Here, we show that clot formation by TF indirectly enhances tumor cell survival after arrest in the lung, during experimental lung metastasis, by recruiting macrophages characterized by CD11b, CD68, F4/80, and CX 3 CR1 (but not CD11c) expression. Genetic or pharmacologic inhibition of coagulation, by either induction of TF pathway inhibitor expression or by treatment with hirudin, respectively, abrogated macrophage recruitment and tumor cell survival. Furthermore, impairment of macrophage function, in either Mac1-deficient mice or in CD11b-diphtheria toxin receptor mice in which CD11b-positive cells were ablated, decreased tumor cell survival without altering clot formation, demonstrating that the recruitment of functional macrophages was essential for tumor cell survival. This effect was independent of NK cells. Moreover, a similar population of macrophages was also recruited to the lung during the formation of a premetastatic niche. Anticoagulation inhibited their accumulation and prevented the enhanced metastasis associated with the formation of the niche. Our study, for the first time, links TF induced coagulation to macrophage recruitment in the metastatic process. (Blood. 2012;119(13): 3164-3175) IntroductionClinical and experimental studies over the past 30 years have established that the coagulation system actively supports tumor progression and metastasis. Consistent with these observations, expression of procoagulants by tumor cells, among them tissue factor (TF), cancer procoagulant, 1 and selectin ligands, correlates with advanced disease and poor outcome for multiple cancer types. 2,3 TF (also known as coagulation factor III or CD142) is the protease receptor that initiates coagulation after injury through the extrinsic pathway. Under normal physiologic conditions, TF expression is limited to extravascular sites that only become exposed to blood after trauma. In this case, the exposed TF binds to and activates the blood-borne coagulation factor FVII, triggering clot formation through a cascade of proteolytic events that results in thrombin formation, activation of platelets, and fibrin deposition. 4 In addition to triggering coagulation, the binding of FVIIa to TF activates intracellular signaling pathways through the TF cytoplasmic domain, by activating G-protein-coupled protease activated receptors (PARs), especially PAR2. 4 These signaling pathways support tumor angiogenesis 5,6 and regulate tumor progression. 7 Intracellular signaling pathways can be distinguished experimentally from the extracellular coagulative roles of TF by specific antibodies 7 or deletion of the cytoplasmic domain that eliminates many forms of TF signaling but still triggers coagulation. 6,8,9 TF enhances tumor growth and angiogenesis, [4][5][6][7]10 and specifically plays an important role in some experiment...
Liver metastasis from colorectal cancer is a leading cause of cancer mortality. Myeloid cells play pivotal roles in the metastatic process, but their prometastatic functions in liver metastasis remain incompletely understood. To investigate their role, we simulated liver metastasis in C57BL/6 mice through intrasplenic inoculation of MC38 colon carcinoma cells. Among the heterogeneous myeloid infiltrate, we identified a distinct population of CD11b/Gr1 mid cells different from other myeloid populations previously associated with liver metastasis. These cells increased in number dramatically during establishment of liver metastases and were recruited from bone marrow by tumor-derived CCL2. Liver metastasis of Lewis lung carcinoma cells followed this pattern but this mechanism is not universal as liver colonization by B16F1 melanoma cells did not recruit similar subsets. Inhibition of CCL2 signaling and absence of its cognate receptor CCR2 reduced CD11b/Gr1 mid recruitment and decreased tumor burden. Depletion of the CD11b/Gr1 mid subset in a transgenic CD11b-diphtheria toxin receptor mouse model markedly reduced tumor cell proliferation. There was no evidence for involvement of an adaptive immune response in the prometastatic effects of CD11b/Gr1 mid cells. Additionally, an analogous myeloid subset was found in liver metastases of some colorectal cancer patients. Conclusion: Collectively, our findings highlight the importance of myeloid cells-in this case a selective CD11b/Gr1 mid subsetin sustaining development of colorectal cancer liver metastasis and identify a potential target for antimetastatic therapy. (HEPATOLOGY 2013;57:829-839) M etastatic colorectal cancer (CRC) is a prominent cause of cancer mortality worldwide. 1 Hepatic metastases are found in approximately 15% of CRC patients at primary diagnosis 2 with 14% subsequently developing metastases.3 Development of new treatment modalities for CRC liver metastasis is urgently required and a greater understanding of the biology of this process will help establish new therapeutics aimed at downstaging the disease, improving operability, and prolonging survival.Metastasis is a multistep process involving complex and continuous interactions between tumor cells and the host microenvironment.4 Several myeloid-derived cell types have been shown to play key roles in the metastatic cascade, including intravasation, extravasation, 5 and colonization at secondary sites by stimulating tumor cell proliferation and angiogenesis and suppressing antitumor immunity.6-8 However, delineation of their roles in metastasis is complicated by the heterogeneity of myeloid phenotypes that appears to be both tumor-and organ-selective. Vascular endothelial growth factor receptor 1 (VEGFR1) þ hematopoietic progenitor cells accumulated at premetastatic sites to promote adherence and growth of lung Lewis carcinoma (LLC) and B16F1 tumor cells, 9 while a Mac-1 þ myeloid population with different markers was
We have established a significant association between osteoporosis and tooth loss after adjusting the effect for age and smoking.
Excessive acetabular cover secondary to a retroverted acetabulum causes pincer impingement, which may cause early osteoarthritis of the hip. Our aim was to determine if there was a relationship between acetabular version and osteoarthritis of the hip. Using image processing and analysis software we studied 117 CT images of the hip in patients aged less than 65 years who had undergone a CT virtual colonoscopy. The mean CT joint space of the 18 hips with acetabular retroversion was narrower compared with the 99 hips with normal acetabular alignment (p < 0.0001). A correlation of r = 0.46 (p < 0.01) was found between right hip acetabular version and the mean right hip joint space and of r = 0.31 (p = 0.02) between left hip acetabular version and the mean left hip joint space. Acetabular retroversion is associated with radiological evidence of osteoarthritis of the hip. An understanding of the mechanical basis of osteoarthritis of the hip allows early treatment of the underlying structural abnormality and prevents progression of the degenerative condition.
Poly(ADP-ribose) polymerase (PARP) inhibitors are increasingly being studied as cancer drugs, as single agents, or as a part of combination therapies. Imaging of PARP using a radiolabeled inhibitor has been proposed for patient selection, outcome prediction, dose optimization, genotoxic therapy evaluation, and target engagement imaging of novel PARP-targeting agents. Methods: Here, via the copper-mediated 18 F-radiofluorination of aryl boronic esters, we accessed, for the first time (to our knowledge), the 18 F-radiolabeled isotopolog of the Food and Drug Administration–approved PARP inhibitor olaparib. The use of the 18 F-labeled equivalent of olaparib allows direct prediction of the distribution of olaparib, given its exact structural likeness to the native, nonradiolabeled drug. Results: 18 F-olaparib was taken up selectively in vitro in PARP-1–expressing cells. Irradiation increased PARP-1 expression and 18 F-olaparib uptake in a radiation-dose–dependent fashion. PET imaging in mice showed specific uptake of 18 F-olaparib in tumors expressing PARP-1 (3.2% ± 0.36% of the injected dose per gram of tissue in PSN-1 xenografts), correlating linearly with PARP-1 expression. Two hours after irradiation of the tumor (10 Gy), uptake of 18 F-olaparib increased by 70% ( P = 0.025). Conclusion: Taken together, we show that 18 F-olaparib has great potential for noninvasive tumor imaging and monitoring of radiation damage.
Key Points• Metastatic tumor cell attachment induces endothelial VCAM-1 and VAP-1.• VCAM-1 and VAP-1 promote metastatic tumor cell survival by recruiting myeloid cells, pointing to VAP-1 as a therapeutic target.Pulmonary metastasis is a frequent cause of poor outcome in cancer patients. The formation of pulmonary metastasis is greatly facilitated by recruitment of myeloid cells, which are crucial for tumor cell survival and extravasation. During inflammation, homing of myeloid cells is mediated by endothelial activation, raising the question of a potential role for endothelial activation in myeloid cell recruitment during pulmonary metastasis. Here, we show that metastatic tumor cell attachment causes the induction of the endothelial activation markers vascular cell adhesion molecule-1 (VCAM-1) and vascular adhesion protein-1 (VAP-1). Induction of VCAM-1 is dependent on tumor cell-clot formation, decreasing upon induction of tissue factor pathway inhibitor or treatment with hirudin. Furthermore, inhibition of endothelial activation with a VCAM-1 blocking antibody or a VAP-1 small molecule inhibitor leads to reduced myeloid cell recruitment and diminished tumor cell survival and metastasis without affecting tumor cell adhesion. Simultaneous inhibition of VCAM-1 and VAP-1 does not result in further reduction in myeloid cell recruitment and tumor cell survival, suggesting that both act through closely related mechanisms. These results establish VCAM-1 and VAP-1 as mediators of myeloid cell recruitment in metastasis and identify VAP-1 as a potential target for therapeutic intervention to combat early metastasis. (Blood. 2013;121(16):3289-3297)
Brain metastasis is a common complication of cancer patients and is associated with poor survival. Histological data from patients with brain metastases suggest that microglia are the major immune population activated around the metastatic foci. Microglia and macrophages have the ability to polarize to different phenotypes and to exert both tumorigenic and cytotoxic effects. However, the role of microglia/macrophages during the early stages of metastatic growth in the brain has not yet been determined. The aim of this study was to profile microglial/macrophage activation in a mouse model of breast cancer brain metastasis during the early stages of tumor growth, and to assess the role of the anti-inflammatory microglial/macrophage population, specifically, during this phase. Following intracerebral injection of 5 × 103 4T1-GFP mammary carcinoma cells into female BALB/c mice, robust microglial/macrophage activation around the 4T1 metastatic foci was evident throughout the time-course studied (28 days) and correlated positively with tumor volume (R2 = 0.67). Populations of classically (proinflammatory) and alternatively (anti-inflammatory) activated microglia/macrophages were identified immunohistochemically by expression of either induced nitric oxide synthase/cyclooxygenase 2 or mannose receptor 1/arginase 1, respectively. Temporally, levels of both pro- and anti-inflammatory cells were broadly stable across the time-course. Subsequently, selective depletion of the anti-inflammatory microglia/macrophage population by intracerebral injection of mannosylated clodronate liposomes significantly reduced metastatic tumor burden (p < 0.01). Moreover, increased levels of apoptosis were associated with tumors in clodronate liposome treated animals compared to controls (p < 0.05). These findings suggest that microglia/macrophages are important effectors of the inflammatory response in the early stages of brain metastasis, and that targeting the anti-inflammatory microglial/macrophage population may offer an effective new therapeutic avenue for patients with brain metastases.
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