Lung cancer is the leading cause of cancer deaths throughout the world. The majority of patients are diagnosed with locally advanced or metastatic disease when surgery, the best curative option, is ...no longer feasible. Thus, the prognosis of lung cancer remains poor and heterogeneous and new biomarkers are needed. As the immune system plays a pivotal role in cancer, the study of tumor microenvironment, with regard to the immune component, may provide valuable information for a better comprehension of the pathogenesis and progression of the disease. Through a detailed and critical evaluation of the most recent publications on this topic, we provide evidences of the prognostic and predictive significance of immune markers in tumor and in peripheral blood of lung cancer patients: from the landscape of immune cells (macrophages, neutrophils, lymphocytes and natural killer) and their cytokines, to the analysis of immune-checkpoints (PD-L1 and CTLA4), up to the genetic and epigenetic regulation of the immune response (immune gene signatures and miRNA). We also argue about the lights and shadows related to immune marker use in clinical practice, emphasizing on one hand the importance of their assessment in the choice of therapeutic treatment, on the other, the difficulty in their determination and reproducibility of literature data. The following review gives a foundation and a suggestion for future studies investigating tumor immunology in lung cancer.
Abstract Several data support a central role for angiogenesis in breast cancer growth and metastasis. Observational studies have demonstrated that microvascular density (MVD) is a prognostic factor ...in invasive breast cancer, whereas others reached the opposite conclusion. Vascular endothelial growth factor is the most important angiogenic factor with proven significance in breast cancer, as it has been assessed in both experimental and clinical studies. Triple-negative breast cancer (TNBC) is a type of breast cancer which lacks estrogen, progesterone, and HER-2/neu receptors. MVD in both basal-like and TNBC is significantly higher than in non–basal-like and non-TNBC. In breast cancer and other malignancies, the development of agents that inhibit tumor angiogenesis has been an active area of investigation. In TNBC, clinical trials combining targeted agents and chemotherapy have failed to show substantial survival improvement. There is evidence that patients with TNBC may have a greater probability of obtaining some kind of clinical efficacy benefit from bevacizumab-based therapy.
Angiogenesis, which plays an important role in tumor growth and progression of breast cancer, is regulated by a balance between pro- and anti-angiogenic factors. Expression of vascular endothelial ...growth factor (VEGF) is up-regulated during hypoxia by hypoxia-inducible factor-1α (HIF-1α). It is known that there is an interaction between HIF-1α and BRCA1 carrier cancers, but little has been reported about angiogenesis in BRCA1-2 carrier and BRCAX breast cancers. In this study, we investigated the expression of VEGF and HIF-1α and microvessel density (MVD) in 26 BRCA1-2 carriers and 58 BRCAX compared to 77 sporadic breast cancers, by immunohistochemistry. VEGF expression in BRCA1-2 carriers was higher than in BRCAX cancer tissues (p = 0.0001). Furthermore, VEGF expression was higher in both BRCA1-2 carriers and BRCAX than the sporadic group (p<0.0001). VEGF immunoreactivity was correlated with poor tumor grade (p = 0.0074), hormone receptors negativity (p = 0.0206, p = 0.0002 respectively), and MIB-1-labeling index (p = 0.0044) in familial cancers (BRCA1-2 and BRCAX). The percentage of nuclear HIF-1α expression was higher in the BRCA1-2 carriers than in BRCAX cancers (p<0.05), and in all familial than in sporadic tumor tissues (p = 0.0045). A higher MVD was observed in BRCA1-2 carrier than in BRCAX and sporadic cancer tissues (p = 0.002, p = 0.0001 respectively), and in all familial tumors than in sporadic tumors (p = 0.01). MVD was positively related to HIF-1α expression in BRCA1-2 carriers (r = 0.521, p = 0.006), and, in particular, we observed a highly significant correlation in the familial group (r = 0.421, p<0.0001). Our findings suggest that angiogenesis plays a crucial role in BRCA1-2 carrier breast cancers. Prospective studies in larger BRCA1-2 carrier series are needed to improve the best therapeutic strategies for this subgroup of breast cancer patients.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
BACKGROUND: Tumor infiltrating lymphocytes (TILs) are widely considered a key sign of the immune interaction between host and tumor, and potentially prognostic biomarkers of good or bad outcome in ...many cancers, included invasive breast cancer (BC). However, results about the association between TIL typology, location and BC prognosis, are controversial. The aim of the study was to evaluated the prognostic significance of TIL subtypes (CD4+, CD8+, FOXP3+ T cells) and their location (stromal “s” and intratumoral “i” CD4+ and CD8+) in BC patients, focusing on the association between these markers and immunocheckpoint molecules such as cytotoxic T lymphocyte antigen 4 (CTLA-4), programmed cell death ligand 1 (PD-L1) and its receptor (PD-1). METHODS: CD4+, CD8+, FOXP3+, CTLA4+, PD-L1+ and PD-1+ expression was examined by immunohistochemistry on tissue microarrays (TMAs) from 180 BC patients. Univariate and Kaplan–Meier analyses of disease free survival (DFS) were performed to evaluate the prognostic significance of marker expression. RESULTS: Total CD8+ T cells were not significantly associated with DFS. Differently, patients with iCD8+ and sCD8+ overexpression showed a trend toward respectively a worse (P = .050) and a better 5-years DFS (P = .064). Interestingly, TIL expression of both PD-1+ and PD-L1+, was significantly associated with iCD8+ (P = .0004; P < .0001 respectively), while only TIL expression of PD-1 was associated with sCD8+ (P = .001). CONCLUSION: Our data show that iCD8+ T cells, but no sCD8+ T cells identify a subgroup of patients with poor DFS and this could be due to the overexpression of PD-L1/PD-1 pathway.
Despite the search for new therapeutic strategies for gastric cancer (GC), there is much evidence of progression due to resistance to chemotherapy. Multidrug resistance (MDR) is the ability of cancer ...cells to survive after exposure to chemotherapeutic agents. The involvement of miRNAs in the development of MDR has been well described but miRNAs able to modulate the sensitivity to chemotherapy by regulating hypoxia signaling pathways have not yet been fully addressed in GC. Our aim was to analyze miR-20b, miR-27a and miR-181a expression with respect to (epirubicin/oxaliplatin/capecitabine (EOX)) chemotherapy regimen in a set of GC patients, in order to investigate whether miRNAs deregulation may influence GC MDR also via hypoxia signaling modulation. Cancer biopsy were obtained from 21 untreated HER2 negative advanced GC patients, retrospectively analyzed. All patients received a first-line chemotherapy (EOX) regimen. MirWalk database was used to identify miR-27a, miR-181a and miR-20b target genes. The expression of miRNAs and of HIPK2, HIF1A and MDR1 genes were detected by real-time PCR. HIPK2 localization was assessed by immunohistochemistry. Our data showed the down-regulation of miR-20b, miR-27a, miR-181a concomitantly to higher levels of MDR1, HIF1A and HIPK2 genes in GC patients with a progressive disease respect to those with a disease control rate. Moreover, immunohistochemistry assay highlighted a higher cytoplasmic HIPK2 staining, suggesting a different role for it. We showed that aberrant expression of miR-20b, miR27a and miR-181a was associated with chemotherapeutic response in GC through HIF1A, MDR1 and HIPK2 genes modulation, suggesting a possible novel therapeutic strategy.
Background & Aims Liver X receptors (LXRs) are transcriptional regulators of cholesterol metabolism, controlling cholesterol flow into cells, catabolism, and efflux. Cholesterol controls cell ...proliferation; disruptions in cholesterol metabolism have been associated with the development of colon cancer. We investigated whether expression of activated LXR protects against intestinal tumorigenesis in mice. Methods We analyzed the development of colon cancer in mice that express a constitutive active form of LXRα only in the intestinal epithelium, under the control of villin promoter (iVP16LXRα). These mice were crossed with adenomatous polyposis coli (Apc)min/+ mice, or given azoxymethane followed by dextran sodium sulfate, to assess intestinal tumor formation. We also assessed proliferation and apoptosis of a human colorectal cancer cell line (HT29) transfected with an adenoviral vector that expressed Ad VP16hLXRα, compared with cells expressing AdVP16 (control), and their ability to form xenograft tumors in mice. HT29 cells also were incubated with the LXR ligand GW3965. Results In human colorectal cancer cells, ligand-induced activation of LXR or transfection with Ad VP16hLXRα blocked the G1 phase, increased caspase-dependent apoptosis, and slowed growth of xenograft tumors in mice. iVP16LXRα mice formed fewer, smaller tumors than VP16 (control) mice after administration of azoxymethane and dextran sodium sulfate. APCmin/+ /iVP16LXRα mice also developed fewer, smaller intestinal tumors than APCmin/+ /iVP16 mice. Gene expression analysis indicated that activation of LXRα affected lipid metabolic networks and increased cholesterol efflux in the intestine. Conclusions Expression of activated LXRα blocks proliferation of human colorectal cancer cells and slows the growth of xenograft tumors in mice. It also reduces intestinal tumor formation after administration of chemical carcinogens, and in Apcmin/+ mice. LXR agonists therefore might be developed as therapeutic treatments for colorectal cancer.
Na+/H+ exchanger regulatory factor 1 (NHERF1) is a scaffold protein, with two tandem PDZ domains and a carboxyl-terminal ezrin-binding (EB) region. This particular sticky structure is responsible for ...its interaction with different molecules to form multi-complexes that have a pivotal role in a lot of diseases. In particular, its involvement during carcinogenesis and cancer progression has been deeply analyzed in different tumors. The role of NHERF1 is not unique in cancer; its activity is connected to its subcellular localization. The literature data suggest that NHERF1 could be a new prognostic/predictive biomarker from breast cancer to hematological cancers. Furthermore, the high potential of this molecule as therapeutical target in different carcinomas is a new challenge for precision medicine. These evidences are part of a future view to improving patient clinical management, which should allow different tumor phenotypes to be treated with tailored therapies. This article reviews the biology of NHERF1, its engagement in different signal pathways and its involvement in different cancers, with a specific focus on breast cancer. It also considers NHERF1 potential role during inflammation related to most human cancers, designating new perspectives in the study of this “Janus-like” protein.
Inflammasome complexes play a pivotal role in different cancer types. NOD-like receptor protein 3 (NLRP3) inflammasome is one of the most well-studied inflammasomes. Activation of the NLRP3 ...inflammasome induces abnormal secretion of soluble cytokines, generating advantageous inflammatory surroundings that support tumor growth. The expression levels of the NLRP3, PYCARD and TLR4 were determined by immunohistochemistry in a cohort of primary invasive breast carcinomas (BCs). We observed different NLRP3 and PYCARD expressions in non-tumor
vs
tumor areas (p<0.0001). All the proteins were associated to more aggressive clinicopathological characteristics (tumor size, grade, tumor proliferative activity etc.). Univariate analyses were carried out and related Kaplan-Meier curves plotted for NLRP3, PYCARD and TLR4 expression. Patients with higher NLRP3 and TLR4 expression had worse 5-year disease-free survival (DFS) compared to patients with lower NLRP3 and TLR4 expression (p =0.021 and p = 0.009, respectively). In multivariate analysis, TLR4 was confirmed as independent prognostic factors for DFS (HR = 2.03, 95% CI 1.16–3.57, p = 0.014), and high NLRP3 expression showed a slight association with DFS (HR = 1.75, 95% CI 0.98–3.15, p = 0.06). In conclusion, we showed TLR4 expression as independent prognostic factors and we highlighted for the first time that high expression of NLRP3 is linked to a poor prognosis in BC patients. These results suggest that NLRP3 and TLR4 could be two new good prognostic factor for BC patients.
The tumor microenvironment (TME) is crucial in cancer onset, progression and response to treatment. It is characterized by an intricate interaction of immune cells and cytokines involved in tumor ...development. Among these, inflammasomes are oligomeric molecular platforms and play a key role in inflammatory response and immunity. Inflammasome activation is initiated upon triggering of pattern recognition receptors (Toll-like receptors, NOD-like receptors, and Absent in melanoma like receptors), on the surface of immune cells with the recruitment of caspase-1 by an adaptor apoptosis-associated speck-like protein. This structure leads to the activation of the pro-inflammatory cytokines interleukin (IL)-1β and IL-18 and participates in different biological processes exerting its effects. To date, the Nod-Like Receptor Protein 3 (NLRP3) inflammasome has been well studied and its involvement has been established in different cancer diseases. In this review, we discuss the structure, biology and mechanisms of inflammasomes with a special focus on the specific role of NLRP3 in breast cancer (BC) and in the sub-group of triple negative BC. The NLRP3 inflammasome and its down-stream pathways could be considered novel potential tumor biomarkers and could open new frontiers in BC treatment.
In clinical practice the gold standard method to assess BRAF status in patients with metastatic melanoma is based on molecular assays. Recently, a mutation-specific monoclonal antibody (VE1), which ...detects the BRAF V600E mutated protein, has been developed. With this study we aimed to confirm the clinical value of the VE1 Ventana® antibody, as today a univocal validated and accredited immunohistochemical procedure does not exist, to preliminary detect BRAF status in our routine diagnostic procedures. Moreover, we explored the biological meaning of BRAF immunohistochemical labeling both as a predictor marker of response to target therapy and, for the first time, as a player of acquired tumor drug resistance.
We analyzed a retrospective series of 64 metastatic melanoma samples, previously investigated for molecular BRAF status, using a fully automatized immunohistochemical method. We correlated the data to the clinicopathologic characteristics of patients and their clinical outcome.
The sensitivity and the specificity of the Ventana® VE1 antibody were 89.2 and 96.2% respectively, while the positive predictive value and negative predictive value were 97.1 and 86.2%, respectively. For six mutated patients the histological sample before treatment and when disease progressed was available. The immunohistochemical BRAF V600E expression in the specimens when disease progressed was less intense and more heterogeneous compared to the basal expression. Multivariate analysis revealed that a less intense grade of positive expression is an independent predictor of a less aggressive stage at diagnosis (p = 0.0413).
Our findings encourage the introduction of immunohistochemistry as a rapid screening tool for the assessment of BRAF status in melanoma patients in routine diagnostic procedures and prepare the ground for other studies to highlight the role of immunohistochemical BRAF V600E expression in patients at the time of progression.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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