Cancer Microenvironment最新文献

For more than 15 years, angiotropism in melanoma has been emphasized as a marker of extravascular migration of tumor cells along the abluminal vascular surface, unveiling an alternative mechanism of tumor spread distinct from intravascular dissemination. This mechanism has been termed extravascular migratory metastasis (EVMM). During EVMM, angiotropic tumor cells migrate in a 'pericytic-like' manner (pericytic mimicry) along the external surfaces of vascular channels, without intravasation. Through this pathway, melanoma cells may spread to nearby or more distant sites. Angiotropism is a prognostic factor predicting risk for metastasis in human melanoma, and a marker of EVMM in several experimental models. Importantly, analogies of EVMM and pericytic mimicry include neural crest cell migration, vasculogenesis and angiogenesis, and recent studies have suggested that the interaction between melanoma cells and the abluminal vascular surface induce differential expression of genes reminiscent of cancer migration and embryonic/stem cell state transitions. A recent work revealed that repetitive UV exposure of primary cutaneous melanomas in a genetically engineered mouse model promotes metastatic progression via angiotropism and migration along the abluminal vascular surface. Finally, recent data using imaging of melanoma cells in a murine model have shown the progression of tumor cells along the vascular surfaces. Taken together, these data provide support for the biological phenomenon of angiotropism and EVMM, which may open promising new strategies for reducing or preventing melanoma metastasis.

Circulating tumor cells (CTC) are of high importance, since they are potential metastatic precursors and are readily available for prognostic analysis and treatment testing. In this review, we demonstrate the great power that green fluorescent protein (GFP) labeling and orthotopic mouse models of cancer confer to the study of CTCs for isolation and characterization, including metastatic testing in mice and the chick embryo as well as drug response testing in vitro. We also describe a facile method to label patient CTCs ex vivo using a telomerase-expressing GFP-containing adenovirus that will allow the CTC studies described in this review to be translated clinically.

Accumulating evidence indicate that the behavior of tumorigenic cells is highly influenced by their microenvironment. In this regard, microenvironmental hypoxia plays a determinant role in the emergence of CTC (circulating tumor cells) and CSC (cancer stem cells). CTCs are believed to be indicators of residual disease and thus pose an increased risk of metastasis. In spite of being rare and exposed to immune attack, these cells are capable to escape the immune system of the host. Although CTC play a pivotal role in the metastatic cascade and their prognostic impact has been repeatedly demonstrated, little is known about their escape mechanisms to immune system of the host. Therefore a better knowledge of the immunogenicity of these cells and their cross talk with immune killer cells as well as with tumor microenvironment may represent an exciting new immunotherapy opportunity. In this chapter, we will discuss how hypoxia is involved in the regulation of tumor progression and induction of EMT and cancer stem cell like features. We will also illustrate the relationship between hypoxia and CTC and review how CTC interact with the cells of immune system (both innate and adaptive) in terms of their survival and EMT phenotype. We will attempt to outline how hypoxic stress may confer resistance to CTC by giving them EMT and CSC like phenotype. Finally we will discuss whether the inhibition of hypoxic signaling pathways in different compartments of the solid tumor microenvironment will have an impact on CTC number, resistant phenotype and CTC lysis by immune effectors.

Here we report that leukemia cell lines and primary CD34+ leukemic blasts exposed to platelet rich plasma (PRP) or platelet lysates (PL) display increased resistance to apoptosis induced by mitochondria-targeted agents ABT-737 and CDDO-Me. Intriguingly, leukemia cells exposed to platelet components demonstrate a reduction in mitochondrial membrane potential (ΔΨM) and a transient increase in oxygen consumption, suggestive of mitochondrial uncoupling. Accompanying the ranolazine-sensitive increase in oxygen consumption, a reduction in triglyceride content was also observed in leukemia cells cultured with platelet components indicating that lipolysis and fatty acid oxidation may support the molecular reduction of oxygen in these cells. Mechanistically, platelet components antagonized Bax oligomerization in accordance with previous observations supporting an antiapoptotic role for fatty acid oxidation in leukemia cells. Lastly, substantiating the notion that mitochondrial uncoupling reduces oxidative stress, platelet components induced a marked decrease in basal and rotenone-induced superoxide levels in leukemia cells. Taken together, the decrease in ΔΨM, the transient increase in ranolazine-sensitive oxygen consumption, the reduction in triglyceride levels, and the reduced generation of superoxide, all accompanying the increased resistance to mitochondrial apoptosis, substantiate the hypothesis that platelets may contribute to the chemoprotective sanctuary of the bone marrow microenvironment via promotion of mitochondrial uncoupling.

Estrogen and various growth factors affecting tumor behavior are present in the breast cancer microenvironment, but their comprehensive effects and signal crosstalks are different in each case. However, there is no system to evaluate the factors, detected in individual breast cancer cases, that regulate ER activity and tumor progression. In this study, we analyzed the effects of individual breast cancer extracts by our original system using an estrogen-signal reporter cell line, MCF-7-E10, which we previously established. MCF-7-E10 cell line is stably transfected by an estrogen response element (ERE)-green fluorescent protein (GFP) gene; it expresses GFP when estrogen receptors (ERs) are activated by estrogen or growth factor signal-mediated ER phosphorylation. Using this cell line, we analyzed the comprehensive effects of factors derived from breast cancer tissues on ER activity and growth of MCF-7-E10 cells for each case. We also analyzed relationships between these activities and clinicopathologic characteristics of patients who provided cancer specimens. The breast cancer extracts, which reflect the combined activities of growth factors present in individual cases, stimulated MCF-7-E10 cell growth in an estrogen-independent manner, and specifically stimulated growth of other breast cancer cell lines, regardless of ER expression. High growth-promoting activities were seen in tumor regions of specimens with tumors > 10 mm in size, HER2 intrinsic subtype, and scirrhous and solid-tubular carcinoma histological subtypes. Anti-human hepatocyte growth factor (HGF) antibody and an inhibitor for insulin-like growth factor-1 (IGF-1) receptor inhibited MCF-7-E10 cell growth by the breast cancer extracts, indicating that signal pathways via HGF or IGF-1 receptor significantly affect breast cancer. These data suggest that growth factors other than estrogen in the tumor extract significantly affect breast cancer aggressiveness in an estrogen-independent manner, and could be useful therapeutic targets.

Studies on interaction of tumor cells with extracellular matrix (ECM) components showed increased extracellular protease activity mediated by the family of matrix metalloproteinases (MMPs). Here we studied the effect of human breast cancer cell line MCF-7-laminin (LM) interaction on MMPs and the underlying signaling pathways. Culturing of MCF-7 cells on LM coated surface upregulated MMP-9 expression as well as reduced tissue inhibitor of metalloproteinases-1 (TIMP-1) expression. LM induced MMP-9 expression is abrogated by the blockade of α2 integrin. Inhibitor studies indicate possible involvement of phosphatidyl-inositol-3-kinase (PI3K), extracellular signal regulated kinase (ERK) and nuclear factor-kappaB (NF-κB) in LM induced signaling. LM treatment also enhanced phosphorylation of FAK (focal adhesion kinase), PI3K, ERK; nuclear translocation of ERK, pERK, NF-κB and cell migration. Our findings indicate that, binding of MCF-7 cells to LM, possibly via α2β1 integrin, induces signaling involving FAK, PI3K, ERK, NF-κB followed by upregulation of MMP-9 and cell migration.

Cancer-associated fibroblasts (CAFs) play an important role in tumor initiation and progression. The aim of this study is to explore the role of 2 CAF markers, fibroblast activated protein (FAP) and α-smooth muscle actin (αSMA), in patients with epithelial ovarian cancer (EOC) post-neoadjuvant chemotherapy. Sixty-six patients with the diagnosis of EOC treated with debulking surgery after neoadjuvant therapy were retrieved from the archives. Immunohistochemistry for FAP and αSMA antibodies were performed on paraffin-embedded tissue. Fisher's exact test was performed to test the association between FAP and αSMA expression and disease status. Kaplan-Meier method with log-rank test was used to check the survival difference between different FAP tumor/stroma expressions. FAP stroma (pos) . expression was strongly associated with higher recurrences rate [OR: 15.95; 95 % CI: 1.521-835.206; p = 0.0072]. Cases with combined FAP stroma (pos) and FAP tumor (neg) had higher death rate [OR: 4.845; 95 % CI: 1.53-16.61; p = 0.0046] and higher recurrence rate [OR: 5.12; 95 % CI: 0.91-54.42; p = 0.0487] compared to all the others. Cases with combined FAP stroma (neg) and FAP tumor (neg) were more likely to have lower recurrence rates [OR: 0.086; 95 % CI: 0.001-0.997; p = 0.0248]. αSMA was expressed by tumor-associated stroma in 95 % of cases and by tumor cells in 9 % of cases. No statistical power was found for αSMA and disease status. Our data indicate that FAP plays an important role in predicting tumor aggressiveness in patients with EOC post-neoadjuvant therapy, and its frequent expression in this malignancy implicates that FAP targeted therapy could be a very attractive strategy.

The scavenger receptor, CD163, is a macrophage-specific marker. Recent studies have shown that CD163 expression in breast and rectal cancer cells is associated with poor prognosis. This study was conducted to evaluate the relationship between CD163 expression as a macrophage trait in cancer cells, and macrophage infiltration and its clinical significance in colorectal cancer. Immunostaining of CD163 and macrophage infiltration were evaluated in paraffin-embedded specimens, earlier analyzed for CD31, D2-40 and S-phase fraction, from primary tumors and normal colorectal mucosa of 75 patients with colorectal carcinoma. The outcomes were analyzed in relation to clinical-pathological data. CD163 expression was positive in cancer cells in 20 % of colorectal cancer patients and was related to advanced tumor stages (P = 0.008) and unfavorable prognosis (p = 0.001). High macrophage infiltration was related to shorter survival and positive CD163 expression in tumor cells. The prognostic impact of macrophage infiltration was independent of tumor stage and CD163 expression in cancer cells (p = 0.034). The expression of macrophage phenotype in colorectal cancer cells is associated with macrophage density in tumor stroma and lower survival rates. Macrophage infiltration has an independent prognostic impact on mortality in colorectal cancer. In accordance with previous experimental studies, these findings provide new insights into the role of macrophages in colorectal cancer.

A potent T cell response is an important component of durable anti-tumor immunity. The quality of the T cell response can, in-part, be measured by the avidity of the T cell for its tumor antigen-expressing target. While convention suggests that raising the avidity of the responding T cells may make for a more potent anti-tumor immune response, the threshold for effective tumor immunity remains unclear, as do some of the adverse effects of an inappropriately high avidity response. In this review, we discuss the relationship between T cell avidity and anti-tumor immunity, considering both experimental model systems as well as human clinical trials.

The tumor stroma plays an essential role in tumor growth, resistance to therapy and occurrence of metastatic phenotype. Tumor vessels have been considered as passive conducts for nutrients but several studies have demonstrated secretion of pro-tumoral factors by endothelial cells. The failure of anti-angiogenic therapies to meet expectations raised by pre-clinical studies prompt us to better study the cross-talk between endothelial and cancer cells. Here, we hypothesized that tumor cells and the endothelium secrete bio-active microparticles (MPs) participating to a functional cross-talk. We characterized the cancer cells MPs, using breast and ovarian cancer cell lines (MCF7, MDA-MB231, SKOV3, OVCAR3 and a primary cell lines, APOCC). Our data show that MPs from mesenchymal-like cell lines (MDA-MB231, SKOV3 and APOCC) were able to promote an activation of endothelial cells through Akt phosphorylation, compared to MPs from epithelial-like cell lines (OVCAR3 and MCF7). The MPs from mesenchymal-like cells contained increased angiogenic molecules including PDGF, IL8 and angiogenin. The endothelial activation was associated to increased Arf6 expression and MPs secretion. Endothelial activation functionalized an MP dependent pro-tumoral vascular niche promoting cancer cells proliferation, invasiveness, stem cell phenotype and chemoresistance. MPs from cancer and endothelial cells displayed phenotypic heterogeneity, and participated to a functional cross-talk where endothelial activation by cancer MPs resulted in increased secretion of EC-MPs sustaining tumor cells. Such cross-talk may play a role in perfusion independent role of the endothelium.