Aberrant expression of vascular cell adhesion molecule-1 (VCAM-1) in breast cancer cells is associated with lung relapse, but the role of VCAM-1 as a mediator of metastasis has remained unknown. We ...report that VCAM-1 provides a survival advantage to breast cancer cells that infiltrate leukocyte-rich microenvironments such as the lungs. VCAM-1 tethers metastasis-associated macrophages to cancer cells via counter-receptor α4-integrins. Clustering of cell surface VCAM-1, acting through Ezrin, triggers Akt activation and protects cancer cells from proapoptotic cytokines such as TRAIL. This prosurvival function of VCAM-1 can be blocked by antibodies against α4-integrins. Thus, newly disseminated cancer cells expressing VCAM-1 can thrive in leukocyte-rich microenvironments through juxtacrine activation of a VCAM-1–Ezrin-PI3K/Akt survival pathway.
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► Breast cancer cells expressing VCAM-1 have a survival advantage in the lungs ► Macrophage binding to VCAM-1 on cancer cells triggers Akt survival signal via Ezrin ► VCAM-1 primes cancer cells for residence in leukocyte-rich microenvironments ► Blocking the VCAM-1-α4-integrin interaction enhances cancer cell death
Tumor-associated macrophages (TAMs) and tumor-associated neutrophils (TANs) have been extensively studied. Their pleotropic roles were observed in multiple steps of tumor progression and metastasis, ...and sometimes appeared to be inconsistent across different studies. In this review, we collectively discussed many lines of evidence supporting the mutual influence between cancer cells and TAMs/TANs. We focused on how direct interactions among these cells dictate co-evolution involving not only clonal competition of cancer cells, but also landscape shift of the entire tumor microenvironment (TME). This co-evolution may take distinct paths and contribute to the heterogeneity of cancer cells and immune cells across different tumors. A more in-depth understanding of the cancer-TAM/TAN co-evolution will shed light on the development of TME that mediates metastasis and therapeutic resistance.
Many cancer types metastasize to bone. This propensity may be a product of genetic traits of the primary tumour in some cancers. Upon arrival, cancer cells establish interactions with various ...bone-resident cells during the process of colonization. These interactions, to a large degree, dictate cancer cell fates at multiple steps of the metastatic cascade, from single cells to overt metastases. The bone microenvironment may even influence cancer cells to subsequently spread to multiple other organs. Therefore, it is imperative to spatiotemporally delineate the evolving cancer-bone crosstalk during bone colonization. In this Review, we provide a summary of the bone microenvironment and its impact on bone metastasis. On the basis of the microscopic anatomy, we tentatively define a roadmap of the journey of cancer cells through bone relative to various microenvironment components, including the potential of bone to function as a launch pad for secondary metastasis. Finally, we examine common and distinct features of bone metastasis from various cancer types. Our goal is to stimulate future studies leading to the development of a broader scope of potent therapies.
Blockade of angiogenesis can retard tumour growth, but may also paradoxically increase metastasis. This paradox may be resolved by vessel normalization, which involves increased pericyte coverage, ...improved tumour vessel perfusion, reduced vascular permeability, and consequently mitigated hypoxia. Although these processes alter tumour progression, their regulation is poorly understood. Here we show that type 1 T helper (T
1) cells play a crucial role in vessel normalization. Bioinformatic analyses revealed that gene expression features related to vessel normalization correlate with immunostimulatory pathways, especially T lymphocyte infiltration or activity. To delineate the causal relationship, we used various mouse models with vessel normalization or T lymphocyte deficiencies. Although disruption of vessel normalization reduced T lymphocyte infiltration as expected, reciprocal depletion or inactivation of CD4
T lymphocytes decreased vessel normalization, indicating a mutually regulatory loop. In addition, activation of CD4
T lymphocytes by immune checkpoint blockade increased vessel normalization. T
1 cells that secrete interferon-γ are a major population of cells associated with vessel normalization. Patient-derived xenograft tumours growing in immunodeficient mice exhibited enhanced hypoxia compared to the original tumours in immunocompetent humans, and hypoxia was reduced by adoptive T
1 transfer. Our findings elucidate an unexpected role of T
1 cells in vasculature and immune reprogramming. T
1 cells may be a marker and a determinant of both immune checkpoint blockade and anti-angiogenesis efficacy.
How organ-specific metastatic traits arise in primary tumors remains unknown. Here, we show a role of the breast tumor stroma in selecting cancer cells that are primed for metastasis in bone. ...Cancer-associated fibroblasts (CAFs) in triple-negative (TN) breast tumors skew heterogeneous cancer cell populations toward a predominance of clones that thrive on the CAF-derived factors CXCL12 and IGF1. Limiting concentrations of these factors select for cancer cells with high Src activity, a known clinical predictor of bone relapse and an enhancer of PI3K-Akt pathway activation by CXCL12 and IGF1. Carcinoma clones selected in this manner are primed for metastasis in the CXCL12-rich microenvironment of the bone marrow. The evidence suggests that stromal signals resembling those of a distant organ select for cancer cells that are primed for metastasis in that organ, thus illuminating the evolution of metastatic traits in a primary tumor and its distant metastases.
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•The primary tumor stroma can determine organ-specific metastatic tropism•CAFs in breast tumors select for bone metastatic cells•CAF-rich tumors mimic the CXCL12-rich microenvironment of the bone marrow•CAF-derived CXCL12 and IGF1 select for high Src activity, a bone metastatic trait
Noncancerous mesenchymal cells in certain breast tumors can influence the direction of metastasis. The cells secrete growth factors that also abound in bone marrow, favoring accumulation of cancer cells that thrive on these factors both in the primary tumor microenvironment and in the bone marrow.
Recently, the subradiant states of one-dimensional two-level atom chains coupled to light modes were found to have decay rates obeying a universal scaling, and an unexpected fermionic character of ...the multiply excited subradiant states was discovered. In this Letter, we theoretically obtain the singly excited subradiant states, and by eliminating the superradiant modes, we demonstrate a relation between the multiply excited subradiant states and the Tonks-Girardeau limit of the Lieb-Liniger model which explains the fermionic behavior. In addition, we identify a new family of subradiant states with correlations different from the fermionic ansatz.
In this paper, we extend previous reference-dependence newsvendor research by incorporating both consumer trade-offs and government subsidies to evaluate the relevant influences on the optimal ...electric vehicle (EV) production decisions. We present the properties of the model, derive the closed-form solutions for the model given the relevant constraints, and use numerical experiments to illustrate the results. We find that subsidies, loss aversion, the performance of both EVs and internal combustion engine-powered vehicles (ICEVs), and the coefficient of variation of demand are significant factors influencing the optimal production quantity and the expected utilities of EV production. The high selling price and other high costs of ICEVs help offset the influence of loss aversion, whereas the high costs of EV enhance loss aversion. Our study enriches the literature on subsidies for EVs by establishing a behavioral model to incorporate the decision bias in terms of loss aversion at the firm level. These findings provide guiding principles for both policymakers and EV managers for making better strategies to promote EVs in the early immature market.
•The performance of both electric vehicles (EVs) and internal combustion engine-power vehicles (ICEVs) influences the EV production decisions.•A loss averse EV manager produces less and obtains less the expected utility than a risk neutral one.•Subsidies help decrease the EV breakeven quantity, increase the optimal quantity, offset the influence of loss aversion.•Subsidies should be adjusted according to the performance of both EVs and the ICEVs, demand heterogeneity, and local conditions.•The high ICEVs costs help offset the influence of loss aversion, whereas the high EV costs enhance loss aversion.
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