Cancer Microenvironment最新文献

Tumor progression is often influenced by infiltration of myeloid cells; depending on the M1- or M2-like activation status, these cells may have either inhibitory or promoting effects on tumor growth. We investigated the properties of tumor-associated myeloid cells in a previously established homotransplantable amelanotic melanoma (RMM tumor line) in F344 rats. RMM tumor nodules were allowed to reach the sizes of 0.5, 1, 2 and 3 cm, respectively. Immunohistochemistry and flow cytometry was performed for macrophage markers CD68 and CD163, and for the antigen-presenting cell marker, MHC class II. Although no significant change was observed in the number of CD68⁺ and CD163⁺ macrophages during RMM progression, the number of MHC class II⁺ antigen-presenting cells was reduced in 3 cm nodules. Real-time RT-PCR of laser microdissection samples obtained from RMM regions rich in MHC class II⁺ cells demonstrated high expressions of M1-like factors: IFN-γ, GM-CSF and IL-12a. Furthermore, fluorescence-activated cell sorting, followed by real-time RT-PCR for CD11b⁺ MHC class II⁺ (myeloid antigen-presenting cells), CD11b⁺ CD163⁺ (M2 type myeloid cells), CD11b⁺ CD80⁺ (M1 type myeloid cells) and CD11b⁺ CD11c⁺ (dendritic cells) cells was performed. Based on the levels of inflammation- and tumor progression-related factors, MHC class II⁺ antigen-presenting cells showed polarization towards M1, while CD163⁺ macrophages, towards M2. CD80⁺ and CD11c⁺ myeloid cells did not show clear functional polarization. Our results provide novel information on tumor-associated myeloid cells in amelanotic melanoma, and may become useful in further research on melanoma immunity.

Some studies have shown that extracellular pH in tumors, which results in tumor progression, is less than that in normal tissues. The aim of this study was to investigate the effects of extracellular acidic pH on proliferation, invasion, and drug-induced apoptosis in acute lymphoblastic cells. The cells were cultured in different pH (pH 6.6 and pH 7.4) for 12 days. Cell proliferation was assessed by MTT assay and cell invasion was assayed by invasion assay and gene expression analysis of MMP-9. Drug-induced apoptosis was evaluated after exposure to doxorubicin for 24 hours by annexin V/PI staining and gene expression analysis of BAX pro-apoptotic protein. The results indicated the enhanced growth and invasion of leukemic cells at pH 6.6 (P ≤ 0.05). Furthermore, the cells at pH 6.6 were resistant to apoptosis by doxorubicin (P ≤ 0.05). It can be concluded that acidic pH increases the proliferation, invasion and reduces the drug-induced apoptosis in acute lymphoblastic leukemia. Extracellular acidity can influence the behavior of leukemic cells and therefore, the manipulation of extracellular liquid can be selected as a therapeutic strategy for leukemia, especially for acute lymphoblastic leukemia.

Apo2L/tumor necrosis factor (TNF)-α-related apoptosis-inducing ligand (TRAIL, TNFSF10) is an important cytokine in the tumor microenvironment and plays a major role in the balance of cell survival/death pathways. Bioinformatic analyses of 839 adenocarcinoma (AC) and 356 squamous cell lung carcinoma patient data (SCC) by cBioPortal (genomic analyses) shows that TRAIL expression leads to differential outcomes of disease free survival in AC and SCC. Oncomine datamining (transcript analyses) reveal that TRAIL is upregulated in 167 SCC as compared to 350 AC patients from six data sets. Genomic analyses using cBioPortal revealed high rates of KRAS mutation in AC accompanied by higher incidence of metastasis and increased amplifications of TRAIL gene in SCC. Bioinformatic analyses of an additional lung cancer patient database also showed that risk of disease progression was significantly increased with high TRAIL expression in AC (461 samples). In vitro studies demonstrated that TRAIL increased phosphorylation of ERK only in adenocarcinoma cell lines with mutant KRAS. This was associated with increased migration that was abrogated by MEK inhibitor PD98059. Effects of increased migration induced by TRAIL persisted even after exposure to ionizing radiation with suppression of DNA damage response. These results help understand the role of TRAIL signaling in metastasis which is essential to develop strategies to revert these signals into pro-apoptotic pathways.

S100A11, a small Ca²⁺ binding protein, acts extracellularly as a mediator of cancer progression. That raises the question of how a protein that lacks the classical secretory signal is able to be secreted outside cells without being damaged. Some insights into this question have been obtained, and there has been accumulating evidence indicating a pivotal role of a non-classical vesicle-mediated pathway using lysosomes or peroxisomes for the protein secretion. To obtain a more precise insight into the secretory mechanism of S100A11, we first screened representative cancer cells exhibiting significantly active secretion of S100A11. From the results of profiling, we turned our attention to aggressive cancer mesothelioma cells. In mesothelioma cells, we found that abundant dimeric S100A11 was produced selectively in the peroxisome after transportation of monomeric S100A11 through an interaction with PEX14, a peroxisome membrane protein, resulting in peroxisomal secretion of dimerized S100A11. In an extracellular environment in vitro, dimerized S100A11 promoted mesothelial cell invasion indirectly with the help of fibroblast cells. Overall, the results indicate that the peroxisome functions as an essential vesicle for the production of dimerized S100A11 and the subsequent secretion of the protein from mesothelioma cells and that peroxisome-mediated secretion of dimerized S100A11 might play a critical role in mesothelioma progression in a tumor microenvironment.

Toll-like receptors (TLRs) are pattern recognition receptors mainly expressed by cells of the immune system but also by epithelial tumor cells. Little is known about expression patterns of TLR genes in breast tumors, and their clinical significance is unclear. The aim of our study was to investigate expression of TLRs pathway components in pre-invasive breast lesions and invasive breast carcinomas (IBCs). We used RT-PCR assays to quantify mRNA levels of the 10 TLR genes and genes involved in TLR pathways in 350 breast tumors from patients with known clinical/pathological status and long-term outcome. Sets of 158 breast samples were also analyzed by immunochemistry including; 40 early noninvasive breast lesions, 38 IBCs and 80 triple negative carcinomas subtype (TNCs). We identified TLR9 as the major TLR gene family member upregulated in breast tumors and more particularly in TNCs. Immunohistochemical studies demonstrated that TLR9 protein was expressed in tumor epithelial and stromal cells of the TLR9 mRNA-overexpressing tumors. TLR9 overexpression appears very early during breast carcinogenesis. High TLR9 levels were associated with favorable outcome in the TNC sub-group. TLR9 overexpression was associated with alterations of down-stream components of the TLR9 signaling pathway, epithelio-mesenchymal transition (EMT) induction and EGFR pathway deregulation. TNCs with TLR9 overexpression were significantly correlated with development of a fibrous and inflammatory microenvironment with variable status of nuclear phosphoSTAT3. Our results suggest that TLR9 could play a role in TNC carcinogenesis and could be useful as predictive biomarker and therapeutic target.

Thymidine phosphorylase (TP) is a nucleoside metabolism enzyme that plays an important role in the pyrimidine pathway.TP catalyzes the conversion of thymidine to thymine and 2-deoxy-α-D-ribose-1-phosphate (dRib-1-P). Although this reaction is reversible, the main metabolic function of TP is catabolic. TP is identical to the angiogenic factor platelet-derived endothelial-cell growth factor (PD-ECGF). TP is overexpressed in several human cancers in response to cellular stressful conditions like hypoxia, acidosis, chemotherapy and radiotherapy. TP has been shown to promote tumor angiogenesis, invasion, metastasis, evasion of the immune-response and resistance to apoptosis. Some of the biological effects of TP are dependent on its enzymatic activity, while others are mediated through cytokines like interleukin 10 (IL-10), basic fibroblast growth factor (bFGF) and tumour necrosis factor α (TNFα). Interestingly, TP also plays a role in cancer treatment through its role in the conversion of the oral fluoropyrimidine capecitabine into its active form 5-FU. TP is a predictive marker for fluoropyrimidine response. Given its various biological functions in cancer progression, TP is a promising target in cancer treatment. Further translational research is required in this area.