Integrin alpha5 in human breast cancer is a mediator of bone metastasis and a therapeutic target for the treatment of osteolytic lesions

Bone metastasis remains a major cause of mortality and morbidity in breast cancer. Therefore, there is an urgent need to better select high-risk patients in order to adapt patient’s treatment and prevent bone recurrence. Here, we found that integrin alpha5 (ITGA5) was highly expressed in bone metastases, compared to lung, liver, or brain metastases. High ITGA5 expression in primary tumors correlated with the presence of disseminated tumor cells in bone marrow aspirates from early stage breast cancer patients (n = 268; p = 0.039). ITGA5 was also predictive of poor bone metastasis-free survival in two separate clinical data sets (n = 855, HR = 1.36, p = 0.018 and n = 427, HR = 1.62, p = 0.024). This prognostic value remained significant in multivariate analysis (p = 0.028). Experimentally, ITGA5 silencing impaired tumor cell adhesion to fibronectin, migration, and survival. ITGA5 silencing also reduced tumor cell colonization of the bone marrow and formation of osteolytic lesions in vivo. Conversely, ITGA5 overexpression promoted bone metastasis. Pharmacological inhibition of ITGA5 with humanized monoclonal antibody M200 (volociximab) recapitulated inhibitory effects of ITGA5 silencing on tumor cell functions in vitro and tumor cell colonization of the bone marrow in vivo. M200 also markedly reduced tumor outgrowth in experimental models of bone metastasis or tumorigenesis, and blunted cancer-associated bone destruction. ITGA5 was not only expressed by tumor cells but also osteoclasts. In this respect, M200 decreased human osteoclast-mediated bone resorption in vitro. Overall, this study identifies ITGA5 as a mediator of breast-to-bone metastasis and raises the possibility that volociximab/M200 could be repurposed for the treatment of ITGA5-positive breast cancer patients with bone metastases

Relation between Overall Rate of ATRP and Rates of Activation of Dormant Species

The rate of atom transfer radical polymerization (ATRP) depends on the rate constant of propagation (k(p)) and concentration of growing radicals. The latter is related to the ATRP equilibrium constant (K-ATRP) and concentrations of alkyl halides, activators, and deactivators. Activation of alkyl halides by Cu-I/L and deactivation of radicals by X-Cu-II/L are vital processes providing good control in ATRP. Rates of these reactions are typically identical throughout polymerization, since the ATRP equilibrium is maintained in essentially all ATRP systems. There are new ATRP processes carried out with ppm of Cu catalysts, such as activators regenerated by electron transfer (ARGET), initiators for continuous activator regeneration (ICAR), supplemental activators and reducing agents (SARA), and electrochemically or photochemically mediated ATRP (eATRP, photoATRP). In these processes, as in conventional radical polymerization (or in RAFT), concentration of radicals is established by balancing rates of radical generation (e.g., from thermal initiators, reduction rate or supplemental activation) and radical termination (i.e., reaching steady state). However, in these processes, the rate of activation of alkyl halides by Cu-I/L is still equal to the rate of deactivation of radicals by X-Cu-II/L. Can the rates of activation of alkyl halides (by Cu-I or by Cu-0) be directly related to the overall rate of ATRP? This report aims to clarify that rate of activation of alkyl halides by Cu species cannot be directly related to the overall rate of polymerization. There are many cases with the same rate of ATRP but dramatically different rates of activation and cases with similar activation rates but very different overall ATRP rates. Thus, both the analytical approach and PREDICI simulations clearly show that rates of normal ATRP with high catalyst loadings as well as rates of low ppm ATRP systems, such as ICAR ATRP and SARA ATRP, cannot be directly related with rates of activation of alkyl halides by Cu-I. In SARA ATRP, the activation of alkyl halides by Cu-I is always much faster than by Cu

Atom Transfer Radical Polymerization: Billion Times More Active Catalysts and New Initiation Systems

Approaching 25 years since its invention, atom transfer radical polymerization (ATRP) is established as a powerful technique to prepare precisely defined polymeric materials. This perspective focuses on the relation between structure and activity of ATRP catalysts, and the consequent choice of the initiating system, which are paramount aspects to well-controlled polymerizations. The ATRP mechanism is discussed, including the effect of kinetic and thermodynamic parameters and side reactions affecting the catalyst. The coordination chemistry and activity of copper complexes used in ATRP are reviewed in chronological order, while emphasizing the structure–activity correlation. ATRP-initiating systems are described, from normal ATRP to low ppm Cu systems. Most recent advancements regarding dispersed media and oxygen-tolerant techniques are presented, as well as future opportunities that arise from progressively more active catalysts and deeper mechanistic understanding

Catalyzed radical termination in the presence of tellanyl radicals

International audienceThe decomposition of the diazo initiator dimethyl 2,2′‐azobis(isobutyrate) (V‐601), generating the Me2C.(CO2Me) radical, affords essentially the same fraction of disproportionation and combination in media with a large range of viscosity (C6D6, [D6]DMSO, and PEG 200) in the 25–100 °C range. This is in stark contrast to recent results by Yamago et al. on the same radical generated from Me2C(TeMe)(CO2Me) and on other X‐TeR systems (X=polymer chain or unimer model; R=Me, Ph). The discrepancy is rationalized on the basis of an unprecedented RTe.‐catalyzed radical disproportionation, with support from DFT calculations and photochemicaL V‐601 decomposition in the presence of Te2Ph2