Cancer Microenvironment最新文献

Though the existence of cancer stem cells remained enigmatic initially, over the time their participation in tumorigenesis and tumor progression has become highly evident. Today, they are also appreciated as the causal element for tumor heterogeneity and drug-resistance. Cancer stem cells activate a set of molecular pathways some of which are triggered by the unique mechanical properties of the tumor tissue stroma. A relatively new field called mechanobiology has emerged, which aims to critically evaluate the mechanical properties associated with biological events like tissue morphogenesis, cell-cell or cell-matrix interactions, cellular migration and also the development and progression of cancer. Development of more realistic model systems and biophysical instrumentation for observation and manipulation of cell-dynamics in real-time has invoked a hope for some novel therapeutic modalities against cancer in the future. This review discusses the fundamental concepts of cancer stem cells from an intriguing viewpoint of mechanobiology and some important breakthroughs to date.

Cancer-derived exosomes are constitutively produced and secreted into the blood and biofluids of their host patients providing a liquid biopsy for early detection and diagnosis. Given their ubiquitous nature, cancer exosomes influence biological mechanisms that are beneficial to the tumor cells where they are produced and the microenvironment in which these tumors exist. Accumulating evidence suggests that exosomes transport proteins, lipids, DNA, mRNA, miRNA and long non coding RNA (lncRNA) for the purpose of cell-cell and cell-extracellular communication. These exosomes consistently reflect the status as well as identity of their cell of origin and as such may conceivably be affecting the ability of a functional immune system to recognize and eliminate cancer cells. Recognizing and mapping the pathways in which immune suppression is garnered through these tumor derived exosome (TEX) may lead to treatment strategies in which specific cell membrane proteins or receptors may be targeted, allowing for immune surveillance to once again help with the treatment of cancer. This Review focuses on how cancer exosomes interact with immune cells in the blood.

Even with rigorous treatments, glioblastoma multiforme (GBM) has an abysmal median survival rate, greatly due to the drug-resistant glioblastoma stem cell (GSC) population. GSCs are known to remodel their microenvironment, but the precise role of extracellular matrix components hyaluronic acid (HA) and hyaluronidases (HAases) on the GSC population is still largely unknown. Our objective was to determine how HAase can sensitize GSCs to chemotherapy drugs by disrupting the HA-CD44 signaling. GBM cell line U87-MG and patient-derived D456 cells were grown in GSC-enriching media and treated with HA or HAase. Expressions of GSC markers, HA-related genes, and drug resistance genes were measured via flow cytometry, confocal microscopy, and qRT-PCR. Proliferation after combined HAase and temozolomide (TMZ) treatment was measured via WST-8. HA supplementation promoted the expression of GSC markers and CD44 in GBM cells cultured in serum-free media. Conversely, HAase addition inhibited GSC gene expression while promoting CD44 expression. Finally, HAase sensitized GBM cells to TMZ. We propose a combined treatment of HAase and chemotherapy drugs by disrupting the stemness-promoting HA to target GSCs. This combination therapy shows promise even when temozolomide treatment alone causes resistance.

Pancreatic ductal adenocarcinoma remains one of the most challenging human cancers. Desmoplasia is predominant in this disease exhibiting a strong stromal reaction with an abundance of the cancer-associated fibroblasts (CAFs). We aimed in this study to investigate the reciprocal interaction between the tumor cells and the CAFs and its effect on tumor cells survival. We hypothesized that the survival of pancreatic cancer cell with aggressive phenotype is modulated by the Interactions between malignant pancreatic tumor cells and surrounding CAFs. To examine this, we utilized co-culture methods where tumor cells with different malignant potentials, HPAF (low) HPAF-CD11 (moderate/high) co-cultured with CAFs. CAFs-conditioned media increased the growth of HPAF-CD11 but not HPAF cells and increased CXCL8 levels highly in HPAF-CD11 and slightly in HPAF. The growth stimulatory effect and elevated CXCL8 level caused by CAFs-conditioned media were diminished by neutralizing the fibroblast growth factor-2 (FGF-2). In addition, conditioned media of HPAF-CD11 increased CAFs cell number whereas that of HPAF did not, and these effects were suppressed by neutralizing CXCL8. Furthermore, data from gene expression microarray study exhibited different expression profiles between HPAF and HPAF-CD11 when co-culture with CAFs. A significant increase in CXCL8 and FGF-2 expression was observed with HPAF-CD11/CAFs co-culture and to a lower extent with HPAF/CAFs co-culture. Together, these data demonstrate a paracrine bi-directional interaction between pancreatic tumor cells and the CAFs through CXCL8 and FGF-2 that helps the tumor growth. Future in-depth study of these pathways will assist in obtaining diagnostic and therapeutic tools for pancreatic ductal adenocarcinoma.

The finding that hypoxia can induce cancer stemness in various experimental models is in agreement with the conceptual basis of cancer cell plasticity. Here, we aimed to gain insights into the molecular basis of hypoxia-induced cancer cell plasticity in triple negative breast cancer (TNBC). To achieve this goal, we employed our previously published in-vitro model of TNBC, in which a small subset of stem-like cells can be distinguished from the bulk cell population based on their responsiveness to a Sox2 reporter. In MDA-MB-231, a TNBC cell line, we observed that hypoxia significantly increased the expression of luciferase and green fluorescence protein (GFP), the readouts of the Sox2 reporter. Upon hypoxic challenge, the bulk, reporter unresponsive (RU) cells acquired stem-like features, as evidenced by the significant increases in the proportion of CD44^high/CD24^low cells, colony formation and resistance to cisplatin. Correlating with these phenotypic changes, RU cells exposed to hypoxia exhibited a substantial upregulation of the active/phosphorylated form of STAT3 (pSTAT3). This hypoxia-induced activation of STAT3 correlated with increased STAT3 transcriptional activity, as evidenced by increased STAT3-DNA binding and an altered gene expression profile. This hypoxia-induced STAT3 activation is biologically significant, since siRNA knockdown of STAT3 in RU cells significantly attenuated the hypoxia-induced acquisition of Sox2 activity and stem-like phenotypic features. In conclusion, our data have provided the proof-of-concept that STAT3 is a critical mediator in promoting the hypoxia-induced acquisition of cancer stemness in TNBC. Targeting STAT3 in TNBC may be useful in overcoming chemoresistance and decreasing the risk of disease relapse.

Ovarian cancer (OC) ascites is an inflammatory and immunosuppressive tumor environment characterized by the presence of various cytokines, chemokines and growth factors. The presence of high concentrations of these cytokines/chemokines in ascites is associated with a more aggressive tumor phenotype. IL-10 is an immunosuppressive cytokine for which high expression has been associated with poor prognosis in some cancers. However, its role on OC tumor cells has not been explored. Therefore, the aim of the current study was to elucidate the role of ascites IL-10 on the proliferation, migration and survival of OC cell lines. Here, we show that IL-10 levels are markedly increased in patients with advanced serous OC ascites relative to serous stage I/II ascites and peritoneal effusions from women with benign conditions. Ascites and IL-10 dose-dependently enhanced the proliferation and migration of OC cell lines CaOV3 and OVCAR3 but had no effect on cell survival. IL-10 levels in ascites positively correlated with the ability of ascites to promote cell migration but not proliferation. Depletion of IL-10 from ascites markedly inhibited ascites-induced OC cell migration but was not crucial for ascites-mediated cell proliferation. Taken together, our findings establish an important role for IL-10, as a component of ascites, in the migration of tumor cells.

Neurofibromatosis type 2 (NF-2) is associated with mainly three types of recurrent benign tumors restricted to the central nervous system: schwannoma, meningioma and ependymoma. The absence of the protein NF2/Merlin causes an uninterrupted cell proliferation cascade originating from an abnormal interaction between an extracellular mucopolysaccharide, hyaluronan (HA), and schwann cell surface CD44 receptor, which has been identified as one of the central causative factors for schwannoma. Most tumors in NF-2 have a predilection to originate from either arachnoid cap cells or schwann cells of the cisternal portion of nerve rootlets that share a continuous exposure to cerebrospinal fluid (CSF). We hypothesize that the CSF HA may play a role in tumorigenesis in NF-2. In a prospective analysis over a period of one year, the levels of medium to low molecular weight HA (LMW HA) was estimated in the CSF of three subjects with central schwannomas and compared against that of age-sex matched controls, using Cetyltrimethylammonium bromide coupled turbidimetric assay and found to be seventeen-fold higher in the schwannoma subjects compared to the controls. HA was observed to be actively secreted by cultured schwannoma cells isolated from tumor tissues commensurate with their proliferation rate. On cell viability index analysis to compare the cell proliferation of astrocytoma cells with LMW HA vs. oligomeric HA (OHA), we found a decrease in cell proliferation of up to 30% with OHA. The study provides initial evidence that CSF HA may have a central role in the tumorigenesis of schwannoma in NF-2.

Microcystic, elongated, fragmented (MELF)-pattern is an unusual morphology of myometrial invasive front in endometrioid endometrial carcinoma (EA). The aim of the study was to investigate potential correlation between MELF-pattern and peritumoral inflammatory immune response. A total of 96 out of 368 patients were included in this study. CD3, CD20, CD57. CD68 and S100 markers were used for the detection of tumor-associated T-lymphocytes (TAT), tumor-associated B-lymphocytes (TAB), tumor-associated NK-lymphocytes (NK), tumor-associated macrophages and dendritic cells respectively. Mann-Whitney tests, receiver operating characteristic (ROC) curve analysis, and Spearman correlation were used as methods for statistical analyses. Odds ratio with 95% confidence interval (95% CI) was determined with the use of a logistic regression model. A p < 0.05 was considered statistically significant. Our results suggested that the number of CD3 and CD68 cells were significantly lower (p < 0.001) in cases of endometrioid carcinoma with MELF-pattern. A significant correlation between the presence of MELF-pattern and decrease of CD3 positive T-lymphocytes (r = 0.691; p < 0.001) was also observed. Additionally, we found an inverse correlation between the presence of MELF-pattern and TAM (r = 0.568; p = 0.001). Therefore, our data suggest that MELF-pattern may be associated with EA stroma fibrosis that contains immune cells infiltration and demonstrated a decrease in the number of TAT and TAM cells. This may indicate the poor clinical prognosis of this disease.

Tumors are complex tissues composed of variable amounts of both non-cellular components (matrix proteins) and a multitude of stromal cell types, which are under an active cross-talk with tumor cells. Tumor-associated macrophages (TAMs) are the major leukocyte population among the tumor-infiltrating immune cells. Once they are infiltrated into tumor stroma they undergo a polarized activation, where the M1 and M2 phenotypes represent the two extreme of the polarization heterogeneity spectrum. It is known that TAMs acquire a specific phenotype (M2), oriented toward tumor growth, angiogenesis and immune-suppression. A growing body of evidences supports the presence of tuning mechanisms in order to skew or restraint the inflammatory response of TAMs and thus forces them to function as active tumor-promoting immune cells. The receptor of advanced glycation end-products (RAGE) is a member of the immunoglobulin protein family of cell surface molecules, being activated by several danger signals and thus signaling to promote the production of many pro-inflammatory molecules. Interestingly, this receptor is paradoxically expressed in both M1 and M2 macrophages phenotypes. This review addresses how RAGE signaling has been drifted away in M2 macrophages, and thus taking advantage of the abundance of RAGE ligands at tumor microenvironment, particularly HMGB1, to reinforce the supportive M2 macrophages strategy to support tumor growth.