Immunohistochemical analysis of the mutant epidermal growth factor, ΔEGFR,in glioblastoma

The naturally occurring mutated form of the epidermal growth factor receptor, ΔEGFR (also named EGFRvIII and de2-7EGFR), greatly enhances glioblastoma (GBM) cell growth in vivo through several activities, such as down-regulating p27 and up-regulating BclX(L) while increasing signaling through the RAS-MAPK and PI3-K cascades. More than half of GBMs, especially of the de novo type, overexpress EGFR, and 50%–70% of these express ΔEGFR. However, little is known about the distribution of ΔEGFR-expressing tumor cells within surgical specimens. In order to address this clinically important issue, we performed immunohistochemical analyses of 53 GBMs obtained during surgery using the anti-ΔEGFR monoclonal antibody, DH8.3. We also simultaneously analyzed wild-type EGFR expression in these tissues using the anti-EGFR monoclonal antibody, EGFR. 113. ΔEGFR and wild-type EGFR expression were observed in 20/53 (38%) and 29/53 (55%), respectively. Nineteen (95%) of the ΔEGFR-positive tumors also expressed wild-type EGFR; one case was ΔEGFR-positive but wild-type EGFR-negative. In 13/20 (65%) of the ΔEGFR-positive tumors, tumor cells were scattered diffusely within the tumors, 6/20 showed geographical distribution of ΔEGFR-positive tumor cells, and one case showed homogeneous staining. In the wild-type EGFR-positive cases, almost all tumor cells expressed EGFR. The differential distribution of cells expressing the two receptors observed here may suggest either that ΔEGFR arises at a low frequency from wild-type EGFR-expressing cells, perhaps during the process of gene amplification, or that there is a paracrine-type of interaction between them.     

TNF: a tumor-suppressing factor or a tumor-promoting factor?

TNF-α is a major inflammatory cytokine named for its ability to induce rapid hemorrhagic necrosis of experimental cancers. During efforts to harness this antitumor activity in cancer treatments in the 1980s, a paradoxical tumor-promoting role of TNF became apparent. The cellular and molecular complexity of mammalian tumor microenvironments makes these opposing effects difficult to study. The fruit fly Drosophila melanogaster provides a simpler model system for studying complex cellular and genetic interactions that lead to tumor formation and progression. The paper from Marcos Vidal's group shows that both the tumor-suppressing and tumor-promoting roles of TNF are conserved in Drosophila, and that oncogenic Ras is the switch. The links between inflammation and cancer are now more fully understood, but it is still not clear whether TNF has potential as a target or a therapeutic in malignant disease, or both. Research in an invertebrate organism may provide important insights.     

Epidermal growth factor receptor regulates β-catenin location,stability, and transcriptional activity in oral cancer

Background  

Many cancerous cells accumulate β-catenin in the nucleus. We examined the role of epidermal growth factor receptor (EGFR) signaling in the accumulation of β-catenin in the nuclei of oral cancer cells.     

Epidermal growth factor receptor, protein kinase B/Akt, and glioma response to erlotinib.

The epidermal growth factor receptor （EGFR） tyrosine kinase inhibitor erlotinib （also known as Tarceva or OSI-774） has shown pronfising response rates in malignant gliomas. We investigated the association between expression of EGFR and downstream signaling components and the response of malignant gliomas to erlotinib in a phase I trial of erlotinib administered either alone or with the alkylafing agent temozolomide.     

Targeting the epidermal growth factor receptor in non-small-cell lung cancer: Who,which, when,and how?

Aberrations in the signaling cascade of the epidermal growth factor receptor are common to several solid tumors. Compounds aimed at targeting this pathway have been approved for use by the US Food and Drug Administration for lung, head and neck, pancreas, and colorectal carcinomas. Unfortunately, only the minority of patients treated with this class of agents will have responses or improvements in survival. This article reviews the data on agents that exploit tumor dependency on epidermal growth factor receptor cascade and describes the knowledge on how to discern the appropriate patient population for receiving these agents.     

Expression of basic fibroblast growth factor, transforming growth factor β1 and their 3 receptors in osteosarcoma and its relationship to angiogenesis

Objective: To investigate the expression of angiogenic factors, basic fibroblast, growth factor (bFGF) and transforming growth factor (TGF)-β₁ in osteosarcoma, its association with neovascularization and prognosis. Methods: The expression of bFGF, β₁ and their receptors, as well as intratumoral microvessel count (MVD) were studied in 80 osteosarcomas by immunohistochemical staining and morphometry. The relationship between the angiogenic factors expression and prognosis was evaluated by a multivariate analysis using Cox proportion hazard model. Results: Among 80 cases of osteosarcoma, 46 cases were positive for TGF/TGF-β (57.5%), and 31 cases for β₁, (RI)(38.8%) respectively. The MVD and bFGF, TGFβ_{1 1} were important indicators to predict the prognosis of patients with osteosarcoma by the Cox proportion hazard model analysis. Conclusion: The angiogenic factors bFGF and TGF-β₁ are involved in the angiogenesis of osteosarcoma, and the angiogenesis influences the prognosis. Also they may be useful in the evaluation of the prognosis of patients with osteosarcoma. This work was supported by a grant from the Youth Scientific Research Foundation of the 9th Five-year Plan of the PLA.     

Vascular endothelial growth factor receptors 1,3 and caveolin-1 are implicated in colorectal cancer aggressiveness and prognosis—correlations with epidermal growth factor receptor, CD44v6, focal adhesion kinase, and c-Met

Vascular endothelial growth factor receptor-1 (VEGFR-1) and caveolin-1 have been shown to act both as tumor-promoting and tumor-suppressing proteins in various malignancies as well as in colorectal cancer (CRC), while VEGFR-3’s lymphagiogenic involvement and connection to tumor parameters has yielded heterogenic results. This study was designed to investigate the expression of these molecules in 183 human CRC tissue specimens and explore their effect in both clinicopathological parameters and disease prognosis. We also utilize our previous results regarding epidermal growth factor receptor (EGFR), c-Met, CD44v6, and focal adhesion kinase, in an attempt to further clarify their distinct role in tumor prognosis and their crosstalk. Caveolin-1 was more freely distributed in the neoplasms of the right colon and restricted towards the left and the rectal cancer samples (p?=?0.022); VEGFR-3 was associated with higher nodal metastasis’ status (p?=?0.001) and staging (p?=?0.006), and loss of VEGFR-1 predicted distant metastasis (p?=?0.026) and advanced stage (p?=?0.049). Prompted by previous reports, we performed all analyses also in the patient group of early (I and II) tumor stage where it was evident that VEGFR-1 was more frequently expressed in patients under 60 years old (p?=?0.014) and VEGFR-3 was significantly elevated in left colon cancers (p?=?0.039) and female patients (p?=?0.038). Within the advanced stage (III and IV), the absence of VEGFR-1 exhibited a tendency for higher M status (p?=?0.067) and lack of caveolin-1 signified worse AJCC classification (p?=?0.053). Additionally, patient survival was influenced from VEGFR-3 (p?=?0.019) for the whole sample, whereas subgroup analyses provided a correlation between caveolin-1 expression and improved survival in the early detection group of patients (p?=?0.022). Using Cox regression for all available markers, EGFR, CD44v6, and VEGFR-1 emerged in this study as potential surrogate markers, the latter having positive prognostic significance. We further explored the multiple receptor correlations that were identified.     

Transforming growth factor β signaling inhibitor, SB-431542, induces maturation of dendritic cells and enhances anti-tumor activity

The transforming growth factor β (TGFβ) stimulates tumor progression and metastasis. Secretion of TGFβ by tumor cells also suppresses an antitumor immune response in which dendritic cells (DCs) play an important role to activate cytotoxic T lymphocytes (CTLs). Herein we report that the small molecule TGFβ signaling inhibitor SB-431542, induces DC maturation in vitro and triggers antitumor activity in vivo. We added SB-431542 to cultures of murine bone-marrow derived DCs (BM-DCs) derived from BALB/c mice and human DCs generated from peripheral monocytes (human DCs) at different concentrations in triplicates and examined expression of co-stimulatory molecules by FACS and production of Interleukin-12 (IL-12) by ELISA. SB induced phenotypic maturation of BM-DCs and human DCs and improved their abilities to produce IL-12 in a dose-dependent manner. SB-431542 also augmented capacity of murine and human DCs to activate naive T cells in allogeneic mixed lymphocyte reaction. Interestingly, SB-431542 augmented the capacity of BM-DCs and human DCs to incorporate FITC-conjugated dextran. Intraperitoneal administration of SB-431542 initiated 3 and 7 days after the implantation of colon-26 cancer cells into the peritoneal cavity of BALB/c mice significantly induced CTL activity against colon-26. We incubated human DCs with SB-431542 and cell lysate of scirrhous gastric cancer cell line OCUM-8, and then examined CTL activities against OCUM-8. CD8 T cells activated by human DCs treated with SB-431542 showed modest augmentation CTL activity against cancer cells. Furthermore, pretreatment of human DCs with SB-431542 upregulated cytotoxic activity against K562 cells, suggesting SB should have potential to activate DCs to natural killer cells. In conclusion, TGFβ receptor I kinase inhibitor such as SB-431542 might induce anti-tumor immune response in immuno-tolerant patients associated with TGFβ activity.     

Melanoma cell-derived factor stimulation of fibroblast glycosaminoglycan synthesis—The role of platelet-derived growth factor

The hyaluronan-rich matrix surrounding many tumours may facilitate tumour growth, invasion and angiogenesis, with the majority of this hyaluronan apparently being synthesised by normal fibroblasts, stimulated to do so by tumour cell-derived factors. Melanoma cell-conditioned medium (CM) stimulates up to a 6-fold increase in fibroblast glycosaminoglycan (GAG) synthesis, with the active factors being present in tumour CM ultrafiltration fractions >30 kDa and <1 kDa. These fractions are poorly active individually, but when recombined, the activity is substantially greater than the additive effect. The objective of this study was to identify the factors present in the ultrafiltration fraction >30 kDa that produce a greater than additive effect with the fraction <1 kDa in stimulating the incorporation of ³H glucosamine into fibroblast GAGs. A number of factors including basic fibroblast growth factor (bFGF), interleukin (IL)-1β, pleiotrophin, platelet-derived growth factor (PDGF), transforming growth factor-β (TGF-β), tumour necrosis factor-α (TNF-α) and vascular endothelial growth factor (VEGF) failed to stimulate any significant increase in GAG synthesis, but when added to the <1 kDa tumour CM fraction, both PDGF and to a lesser extent, bFGF, exhibited potent stimulating activities. Neutralising antibodies to PDGF and bFGF added to the melanoma CM decreased the fibroblast GAG-stimulating activity by 29% and 40%, respectively, in C8161 melanoma CM and by 47% and 45%, respectively, in Hs294T melanoma CM. The activities of PDGF-AA and PDGF-BB isoforms were indistinguishable, suggesting the PDGF-α receptor plays a role in the GAG-stimulatory response. Western analysis following treatment with PDGF, bFGF or melanoma CM revealed banding patterns for PDGF and melanoma CM that were similar. Immunoprecipitation of the PDGF-α receptor revealed it to be phosphorylated in fibroblasts treated with PDGF and melanoma CM, but not with control fibroblast CM. These studies suggest that PDGF plays an important role in the GAG-stimulating activity of the melanoma CM, but requires the presence of an as yet unidentified novel low molecular weight factor for full activity.     

Is cancer a prognostic factor for severe COVID-19, especially for breast cancer patients?

The coronavirus disease 2019 (COVID-19) pandemic has caused a global upheaval in our health care system. Our hospital facilities have been subjected to a major influx of patients and the prevention of cross-contamination has been a key issue in the spread of the virus. New recommendations for good hygiene practice and new recommendations for disease management have emerged to limit the spread of the virus and reorganize the provision of care in key services. Many studies have attempted to identify factors that contribute to poor prognosis for COVID-19 infection. Among them, cancer patients, were considered more at risk of developing severe forms of COVID-19. In this article, we provide an overview of the current state of the pandemic as well as new recommendations for disease management that have emerged in oncology and radiation therapy in particular. In this article, we will try to provide some answers through a review of the literature to the question: is cancer a prognostic factor for severe COVID-19?     

The granulocyte-associated transcription factor Krüppel-like factor 5 is silenced by hypermethylation in acute myeloid leukemia

Krüppel-like factor 5 (KLF5) has been implicated as a tumor suppressor in various solid tumors such as breast and prostate, and recent studies have demonstrated a role for this protein in neutrophil differentiation of acute promyelocytic leukemia cells in response to ATRA. Here, we show that KLF5 expression increases during primary granulocyte differentiation and that expression of KLF5 is a requirement for granulocyte differentiation of 32D cells. In AML, we show that KLF5 mRNA expression levels are reduced in multiple French-American-British subtypes compared to normal controls, and also in leukemic stem cells relative to normal hematopoietic stem cells. We demonstrate that in selected AML cases, reduced expression is associated with hypermethylation of the KLF5 locus in the proximal promoter and/or intron 1, suggesting that this may represent a Class II genetic lesion in the development of AML.     

Expression of basic fibroblast growth factor,CD31, and α-smooth muscle actin and esophageal cancer recurrence after definitive chemoradiation

There is cumulative evidence that stromal reaction in cancer has an important diagnostic and prognostic significance. The aims of this study were to analyze the expression of basic fibroblast growth factor (FGF-2), CD31, and α-smooth muscle actin (SMA) in esophageal cancer patients and to establish their significance as indicators of disease recurrence after definitive chemoradiation (CRT). Protein expressions of FGF-2, CD31, and SMA were evaluated by immunohistochemistry and Western blot analysis in 70 patients, 20 with esophageal squamous cell carcinoma (ESCC) and 50 with locally recurrent ESCC after definitive CRT. Twenty matched normal esophageal squamous epithelium were also studied as controls. Esophageal cancer tissues showed positive expression of FGF-2, CD31, and SMA; in contrast, FGF-2 expression was not detected and only little staining for CD31 and SMA was noted in normal epithelium. Protein levels of FGF-2, CD31, and SMA were significantly elevated in recurrent ESCC. Among the patients with locally recurrent disease, expression of FGF-2 and SMA was notably high in whom the tumor recurred locally within 24 months after definitive CRT. The 2- and 5-year local recurrence-free survival rate was 15.4 % and 0 in patients with high FGF-2 expression, compared with 45.8 and 33.3 % in those who expressed low FGF-2, respectively (P?=?0.005). Of patients who expressed high SMA, the 2- and 5-year local recurrence-free survival rate was 21.7 and 8.7 %, respectively, compared to those with low SMA expression which was 37.0 and 22.2 %, respectively (P?=?0.016). Overexpression of FGF-2 and SMA is associated with local recurrence and reduced recurrence-free survival after definitive CRT for ESCC. The data also suggest that targeting stromal cells may be an attractive approach for esophageal cancer therapy strategies.     

Integrin-mediated activation of latent transforming growth factor β

Members of the integrin family recognize a variety of spatially-restricted extracellular ligands. Classically, ligation of integrins activates cytoplasmic signals in the integrin-expressing cell and contributes to cell adhesion, migration, proliferation and survival. At least two members of this family, αvβ6 and αvβ8 perform an additional function, activation of latent complexes of transforming growth factor β. In effect, this process allows integrins on one cell to activate signals on adjacent (in the case of αvβ6) or nearby cells (in the case of αvβ8). Integrin-mediated TGFβ activation has been shown to play important roles in modulating tissue fibrosis, acute lung injury and pulmonary emphysema. Given the important roles that TGFβ plays in modulating epithelial cell growth, epithelial-to-mesenchymal transformation and tumor invasion and metastasis, integrin-mediated TGFβ activation is likely to play important roles in tumor growth ad metastasis.     

Clinicopathological significance of chemotactic factor IL-8, MCP-1 and MIP-1α expressions in gallbladder carcinoma

Objective:Gal bladder carcinoma was one of the malignant tumors in the digestive system, characterized by high recurrence and invasion. Recent research indicates that chemotactic factors such as IL-8, ...