Rapamycin increases leukemia cell sensitivity to chemotherapy by regulating mTORC1 pathway-mediated apoptosis and autophagy.

This study investigated the effect of rapamycin alone and in combination with chemotherapy (doxorubicin and cytarabine) on AML. Human acute monocytic leukemia cell line SHI-1 and NPG AML model mice created by intravenous injection of SHI-1 cell were treated with rapamycin, chemotherapy, or rapamycin plus chemotherapy. Analysis by cell counting kit-8, western blot, flow cytometry, and immunohistochemistry was performed, and results suggested that both rapamycin and chemotherapy inhibited proliferation of SHI-1 cells both in vitro and in vivo, suppressed neoplasm growth in vivo, and promoted survival of NPG AML mice. The antitumor effect of rapamycin plus chemotherapy was better than that of rapamycin alone and chemotherapy alone. In addition, western blot results demonstrated that rapamycin inhibited the phosphorylation of mTOR downstream targets 4EBP1 and S6K1 in SHI-1 cells, and increased the pro-apoptosis-related protein Bax and autophagy-associated proteins Beclin-1, LC3B-II, and ATG5 while reducing the anti-apoptosis-related protein Bcl-2. In conclusion, the results of this study indicate that rapamycin acts synergistically with doxorubicin and cytarabine in AML treatment, and its underlying mechanism might be associated with mTORC1 pathway-mediated apoptosis and autophagy.

Pre-metastatic niche: from revealing the molecular and cellular mechanisms to the clinical applications in breast cancer metastasis.

Breast cancer (BC) is one of the most commonly diagnosed cancers and the leading cause of cancer-related deaths in women worldwide. Metastasis is a major contributor to high cancer mortality and is usually the endpoint of a series of sequential and dynamic events. One of the critical events is forming a pre-metastatic niche (PMN) that occurs before macroscopic tumor cell invasion and provides a suitable environment for tumor cells to colonize and progress into metastases. Due to the unique characteristics of PMN in cancer metastasis, developing therapies to target PMN may bring new advantages in preventing cancer metastasis at an early stage. Various biological molecules, cells, and signaling pathways are altered in BC, regulating the functions of distinctive immune cells and stromal remodeling, inducing angiogenesis, and effect metabolic reprogramming and organotropism to promote PMN formation. In this review, we elucidate the multifaceted mechanisms contributing to the development of PMN in BC, discuss the characteristics of PMN, and highlight the significance of PMN in providing potential diagnostic and therapeutic strategies for BC metastasis, which may bring promising insights and foundations for future studies.

Role of neutrophils on cancer cells and other immune cells in the tumor microenvironment.

The notion that neutrophils only perform a specific set of single functions in the body has changed with the advancement of research methods. As the most abundant myeloid cells in human blood, neutrophils are currently emerging as important regulators of cancer. Given the duality of neutrophils, neutrophil-based tumor therapy has been clinically carried out in recent years and has made some progress. But due to the complexity of the tumor microenvironment, the therapeutic effect is still not satisfactory. Therefore, in this review, we discuss the direct interaction of neutrophils with the five most common cancer cells and other immune cells in the tumor microenvironment. Also, this review covered current limitations, potential future possibilities, and therapeutic approaches targeting neutrophil function in cancer therapy.

Tumor-derived Cav-1 promotes pre-metastatic niche formation and lung metastasis in breast cancer.

Rationale: Breast cancer (BC), as one of the most frequently diagnosed cancer, has a poor prognosis due to the development of distant metastasis. Among the BC metastatic sites, lung is one of the most common sites. Caveolin-1 (Cav-1) is a functional membrane protein that plays a vital role in tumor metastasis. Although studies have revealed that Cav-1 levels were elevated in patients with advanced cancer, whether Cav-1 affects BC lung metastasis by influencing the formation of pre-metastatic niche (PMN) through exosomes has not been explored. Methods: Differential ultracentrifugation, transmission electron microscopy and nanoparticle tracking analysis were used to verify the presence of exosomes. Transwell assays were used to examine the biological effects of exosomes containing Cav-1. Both in vitro cell cultures and mammary tumor cell-induced mouse models were used to assess the lung metastasis. The regulatory mechanisms of PMN formation were revealed using western blot, flow cytometry, RT-qPCR, immunofluorescence assays, gene overexpression assays and RNA interference assays. Results: Exosomes have critical functions in transporting Cav-1 between primary BC and metastatic organ microenvironments. Cav-1 in BC-derived exosomes can act as a signaling molecule to mediate intercellular communication and regulate the PMN before lung metastasis by regulating the expression of PMN marker genes and inflammatory chemokines in lung epithelial cells, promoting the secretion of tenascin-C (TnC) in lung fibroblasts to cause extracellular matrix (ECM) deposition, and inhibiting the PTEN/CCL2/VEGF-A signaling pathway in lung macrophages to facilitate their M2-type polarization and angiogenesis. Conclusion: Our study investigated the mechanisms of lung PMN formation induced by Cav-1 in BC-derived exosomes. Our data may provide new directions for exploring the mechanisms and developing treatment strategies of BC lung metastasis.