Angiogenesis In Oral Cancer Research Articles

Exosomal microRNAs (exoMIRs): micromolecules with macro impact in oral cancer.

Exosomes are a sub-population of extracellular vesicles. It is released from all types of cells and are observed to be involved in cellular communications. It contains DNA, RNA, proteins and lipids. Tumor-derived exosomes can modify the tumor micro-environment and promotetumor development. Exosomal miRNAs are functionally linked with cancer progression, metastasis, and aggressive tumor phenotypes. In this review, we initially discuss onthe fundamental biology of exosomes and then summarize the recent understanding of the exosomal miRNAs in oral cancer with various biological events. Moreover, the dynamic impact of exosomal miRNAs in the oral cancer micro-environment and their multiple parameter alterations can lead to (i) increased uncontrolled cell proliferation, (ii) oral cancer angiogenesis, (iii) oral cancer metastasis, (iv) drug resistance in oral cancer, (v) reprogramming of the immune system in oral cancer, and (vi) clinical significance of exosomal miRNA in oral cancer detection. Exosomes research can pave way to identify early detection toolsin future and personalized medicine development for oral cancer. Thus, our review provides an informative biological insight into exosomal miRNAs in oral cancer, which can benefit the researchers working in the corresponding domain.

Endoglin Expression as a Measure of Microvessel Density in Oral Head and Neck Cancer by Immunohistochemical Study.

Abstract Background and Aim: Tumor growth is limited by the balance between the need for oxygen and nutrients and diffusion of these substances from vessels around tumors. Therefore, angiogenesis, development of new blood vessels from previous blood vessels, is necessary for tumor growth and metastasis. This study was carried out with the aim of evaluating the angiogenesis in oral cancer by assessing microvessel density (MVD) using Endoglin (CD105). This work also correlated the expressions of marker with histopathological grades of oral squamous cell carcinoma. Material and Methods: Immunohistochemical staining with Streptavidin peroxidase was used to analyze the CD105 expression in 25 cases of oral squamous cell carcinoma. Results: All studied cases showed positive of CD105 immunoreactivity. The study revealed a highly significant increase of CD105-MVD in poorly differentiated OSSC than well differentiated OSCC. Conclusion: Increased expression of CD 105 in high grade tumors suggests that Endoglin is likely to contribute significantly to resistance in response to therapy.

Impacts of survivin and caspase-3 on apoptosis and angiogenesis in oral cancer.

The present study aimed to investigate the impact of survivin and caspase-3 on apoptosis and angiogenesis in oral cancer. A total of 16 oral leukoplakia cases accompanied by low-moderate epithelial dysplasia, 12 cases of oral leukoplakia accompanied by severe epithelial dysplasia, 17 cases of high-moderate differentiated oral squamous cell carcinoma and 10 cases of normal oral mucosa were selected. Immunohistochemistry was used to detect the expression levels of survivin, caspase-3, and caspase inhibitor factor VIII in lesions from each group. Terminal deoxynucleotidyl transferase 2'-deoxyuridine, 5'-triphosphate nick end labeling was performed to detect the apoptotic index of oral leukoplakia and cancer tissue. Immunohistochemistry revealed increased expression levels of survivin in oral cancer tissues, as compared with the normal mucosa, whereas the expression of Caspase-3 was decreased during malignant transformation. Microvascular density (MVD) was increased from 28.49±11.87 strips/mm2 (mean ± standard deviation, normal control group) to 91.98±40.20 strips/mm2 (oral cancer group). Therefore, survivin may serve an important role in oral cancer, as its expression was increased in association with a downward trend in caspase-3 expression and apoptotic index, whereas MVD was significantly increased.

Macrophages and endothelial cells orchestrate tumor-associated angiogenesis in oral cancer via hedgehog pathway activation.

The present study aimed to evaluate the role of Hedgehog (Hh) molecule expression in association with the clinical aspects of oral squamous cell carcinoma (OSCC), as well as angiogenesis and CD163+ macrophages. Twenty-eight cases of OSCC, nine cases of tumor-free resection margins (TM), and four cases of non-neoplastic oral mucosa (NNM) were submitted to immunohistochemistry to detect proteins Sonic Hedgehog (SHH), Indian Hedgehog (IHH), GLI1, CD163, and CD105. Protein colocalization with respect to SHH/CD163, IHH/CD163, GLI1/CD163, and GLI1/CD105 was assessed by immunohistochemical double staining. In tumor parenchyma, SHH and IHH were present in the cytoplasm of neoplastic cells, while GLI1 was observed in cytoplasm and nucleus. Endothelial cells were found to express SHH, IHH, and GLI1 within CD105+ vessels, and a positive correlation between infiltrating macrophage density (IMD) and microvascular density (MVD) was observed in cases of OSCC and TM. When compared to TM and NNM, the OSCC cases demonstrated higher immunoreactivity for SHH (p = 0.01), IHH (p = 0.39), GLI1 (p = 0.03), IMD (p = 0.0002), and MVD (p = 0.0002). Our results suggest the participation of the Hh pathway in OSCC by way of autocrine and paracrine signaling, in addition to the participation of both SHH and IHH ligands. Endothelial cells were also found to exhibit positivity with respect to Hh pathway components and we surmise that these molecules may play a role in tumor angiogenesis. CD163+ macrophages were also observed to express IHH, a ligand of this pathway, in addition to being associated with tumor neovascularization.

Abstract B27: Activin A induces vascular endothelial cell proliferation and angiogenesis in oral cancer

Abstract Solid tumors must develop direct and indirect ways to induce angiogenesis in order to continue progression and expansion. The expression of angiogenic factors in the tumor microenvironment is a complex process involving interactions among different cell types. Previous studies demonstrated activin A, a member of the TGF-β superfamily, participates in the development and progression of oral squamous cell carcinomas (OSCC) via regulation of the tumor microenvironment, but its effects in the modulation of angiogenesis are unknown. We examined whether activin A, recombinant or derivate from OSCC cells, promotes angiogenesis of the human umbilical vein endothelial cells (HUVECs). Activin A-treated cells increased tubulogenesis activity concomitantly with high cellular proliferation and low apoptosis. Conversely, follistatin, an activin A antagonist, and activin A knock down in HUVECs significantly inhibited proliferation, induced apoptosis and decreases tube formation. Similarly, conditioned media harvested from OSCC cells expressing high activin A levels increased the proliferative rate and the tubulogenic activity of HUVECs more than those obtained from OSCC cells expressing a shRNA to neutralize activin A expression. In conclusion, our results show that activin A derived from OSCC cells promotes endothelial cell proliferation and tumor angiogenesis, suggesting that activin A signaling could be an important target for tumor vascular disruption in oral cancer. Financial support: FAPESP #2013/19856-2 and #2013/01607-6. Citation Format: Carine Ervolino de Oliveira, Nilva de Karla Cervigne, Carolina Carneiro Souza Macedo, Adriana Franco Paes Leme, Edgard Graner, Ricardo Della Coletta. Activin A induces vascular endothelial cell proliferation and angiogenesis in oral cancer. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Angiogenesis and Vascular Normalization: Bench to Bedside to Biomarkers; Mar 5-8, 2015; Orlando, FL. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl):Abstract nr B27.

Periostin is frequently overexpressed and enhances invasion and angiogenesis in oral cancer

Oral squamous-cell carcinoma (OSCC) is one of the most common types of human cancer. Typically OSCC cells show persistent invasion that frequently leads to local recurrence and distant lymphatic metastasis. We previously identified Periostin as the gene demonstrating the highest fold change expression in the invasive clone by comparing the transcriptional profile of parent OSCC cell line and a highly invasive clone. Here, we demonstrated that Periostin overexpression enhanced invasiveness in oral cancer cell lines. To know the role of Periostin in invasion, angiogenesis and metastasis in OSCC cases, we first examined the expression of Periostin mRNA in 31 OSCC cases by RT–PCR and Periostin protein in 74 OSCC cases by immunohistochemistry. Then, we compared the Periostin expression with invasion pattern, metastasis and blood vessel density. Periostin mRNA and protein overexpression were frequently found in OSCC cases and Periostin expression was well correlated with the invasion pattern and metastasis. Moreover, blood vessel density of Periostin-positive cases was higher than those of Periostin-negative cases. Interestingly, recombinant Periostin enhanced capillary formation in vitro in a concentration-dependant manner. In summary, these findings suggest that Periostin may promote invasion and angiogenesis in OSCC, and that Periostin can be a strong marker for prediction of metastasis in oral cancer patients.

Vascularity and expression of vascular endothelial growth factor in oral squamous cell carcinoma, resection margins, and nodal metastases

The role of vascularity as a predictor of the likelihood of lymph node metastases in oral cancer is not clear. To that end, the vascularity and expression of vascular endothelial growth factor (VEGF) was assessed at three specific regions: the tumour (inside and around the tumour); the resection margin; and the regional lymph nodes. Formalin-fixed paraffin-embedded specimens from 26 oral cancers (11 with no involved nodes and 15 with involved nodes) were stained immunohistochemically and examined. Staining for VEFG was significantly greater in the tumour than in the other sites. No significant differences were found in the intensity of staining in the primary tumour, resection margins, or nodes between cases in which the nodes were involved and in which they were not involved. We found no correlation between vascularity and VEGF staining, suggesting that VEGF is not the primary or only stimulator of angiogenesis in oral cancer. Greater understanding of the mechanisms of metastasis will lead to new treatments. The evidence that is accumulating for oral cancer suggests that such treatments may be better targeted at preventing lymphatic spread, rather than vascular spread.

Angiogenesis in Oral Cancer

Head and neck squamous cell carcinoma (HNSCC) is an aggressive malignancy that develops after years of chronic exposure to alcohol and tobacco products. Exposure to these agents results in alterations of genes that are important in the regulation of various cellular functions. This loss of regulation allows the tumor cells to survive and grow in an unchecked manner by allowing the cells to perform functions that contribute to the growth of the tumor. Some of these important changes include the acquisition of immortality and the ability to invade tissue and/or metastasize to other sights, as well as acquiring the ability to induce angiogenesis. Angiogenesis, the growth of new blood vessels from pre-existing ones, is a complex phenomenon that is absolutely required for the continued growth and survival of solid neoplasms. Without new blood vessels to provide nutrients and remove waste, tumors would be unable to grow larger than 2-3 mm in diameter. Therefore, one could envision its potential role in both the treatment and prevention of malignancies such as HNSCC. The concept of chemoprevention is extremely important in HNSCC since patients often develop multiple independent lesions throughout the mucosa of the upper aerodigestive tract. Therefore, the comprehensive treatment of this disease must address not only the initial primary neoplasm, but also prevent the progression of the premalignant lesions lurking throughout the rest of the mucosal surfaces. This review will outline the basic changes that occur in tumor cells that result in the switch to angiogenic phenotype. In addition, it will discuss the present status of using antiangiogenic agents in the treatment of cancer. Finally, this paper will present a rationale for the use of multiple antiangiogenic agents as a means of developing new chemotherapeutic and chemopreventive protocols that may result in reduced patient toxicity while maintaining similar clinical efficacies.