cp-673-451 and Neoplasm-Metastasis

Lack of insight into the identity of the cells that initiate metastasis hampers the development of antimetastatic therapies. Only a tiny fraction of tumor cells termed metastasis-initiating cells (MICs) are able to successfully seed metastases, causing recurrence and therapeutic resistance. Using metastasis models, we describe a subpopulation of MIC derivates from lung metastases that do not have proliferation advantages, express high levels of the PDGF receptors and EMT/stemness-related genes, and are unique in their ability to initiate metastasis. PDGF factors specifically boost the metastatic potential of MIC populations in a PDGFR-dependent manner. However, PDGFR inhibition preferentially suppresses lung metastases, but does not reduce the primary tumor burden. Thus, we found that PDGFR inhibition blocks AKT activation, whereas SGK1, which shares high-similarity kinase domain and overlap substrates with AKT overexpression remains active in MICs. SGK1 and PDGF signaling act in concert to promote metastatic formation, and SGK1 inhibition confers vulnerability to PDGFR inhibitors, also eliciting a powerful antitumor effect. In vivo, SGK1 inhibitors sensitize xenograft tumors to PDGFR-targeted therapies by reducing primary tumor growth and lung metastasis. Consequently, dual inhibition of PDGFR and SGK1 exhibited strong antitumor activities in established breast cancer cell lines in vitro and in vivo. Therefore, this approach not only provides insight into MIC transformation but also aids the design of improved therapeutic strategies for advanced breast cancer.

Topics: Animals; Antineoplastic Agents; Benzimidazoles; Benzoates; Breast Neoplasms; Bridged Bicyclo Compounds, Heterocyclic; Cell Line, Tumor; Cell Proliferation; Cell Survival; Drug Synergism; Female; Gene Expression Regulation, Neoplastic; Humans; Immediate-Early Proteins; Ligands; Lung Neoplasms; Mice, Inbred NOD; Mice, SCID; Models, Biological; Neoplasm Metastasis; Protein Serine-Threonine Kinases; Quinolines; Receptors, Platelet-Derived Growth Factor

Pericytes are pivotal mural cells of blood vessels and play an essential role in coordinating the function of endothelial cells. Previous studies demonstrated that Endostar, a novel endostatin targeting endothelial cells, can enhance the effect of radiotherapy (RT). The present study addressed whether inhibiting pericytes could potentially improve the efficacy of combined RT and Endostar therapy.. Platelet-derived growth factor beta-receptor inhibitor (CP673451) was chosen to inhibit pericytes and RT (12 Gy) was delivered. Lewis lung carcinoma-bearing C57BL/6 mice were randomized into 3 groups: RT, RT + Endo, and RT + Endo + CP673451. Subsequently, tumor microvessel density (MVD), pericyte coverage, tumor hypoxia, and lung metastasis were monitored at different time points following different therapies.. Compared to the other two groups, RT + Endo + CP673451 treatment markedly inhibited tumor growth with no improvement in the overall survival. Further analyses clarified that in comparison to RT alone, RT + Endo significantly reduced the tumor MVD, with a greater decrease noted in the RT + Endo + CP673451 group. However, additional CP673451 accentuated tumor hypoxia and enhanced the pulmonary metastasis in the combined RT and Endostar treatment.. Tumor growth can be further suppressed by pericyte inhibitor; however, metastases are potentially enhanced. More in-depth studies are warranted to confirm the potential benefits and risks of anti-pericyte therapy.

Topics: Angiogenesis Inhibitors; Animals; Benzimidazoles; Carcinoma, Lewis Lung; Cell Hypoxia; Cell Line, Tumor; Cell Proliferation; Combined Modality Therapy; Endostatins; Female; Lung Neoplasms; Mice, Inbred C57BL; Neoplasm Metastasis; Neovascularization, Pathologic; Pericytes; Quinolines; Receptor, Platelet-Derived Growth Factor beta; Recombinant Proteins; Time Factors