Progression of Metastasis of Oral Tongue Cancer

口腔舌癌转移进展

• 批准号: 6877955
• 负责人: Jeffrey Nicholas Myers
• 金额: $ 32.28万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-05-10 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6877955
• 关键词: actinomycin; apoptosis; athymic mouse; biological signal transduction; cell line; clinical research; genetic transcription; genetic translation; human tissue; immunocytochemistry; in situ hybridization; metastasis; microarray technology; neoplastic process; northern blottings; squamous cell carcinoma; survivin; tongue neoplasms; western blottings

DESCRIPTION (provided by applicant): Current theories of tumor progression postulate that normal epithelial cells need to acquire mechanisms to evade apoptosis and acquire several other essential biologic properties in order to progress to invasive and metastatic tumors. Programmed cell death after detachment from the basement membrane is known as an oikis. The central hypothesis is of this application is that evasion of anoikis is associated with local tumor progression, and metastasis of squamous cell carcinoma of the oral cavity (SCCOC). Four individual inter-related hypotheses would be evaluated in four separate Aims. The first hypothesis is that anoikis-resistance is necessary but not sufficient for tumor progression, including local growth as well as regional and distant metastases. To demonstrate that anoikis-resistance is associated with disease progression, we will investigate the growth of human SCCOC cell lines in an orthotopic, nude mouse model that we have developed. Human SCCOC cell lines and anoikis resistant cells that have been selected in vitro will be injected into the tongues of nude mice, and these mice will be examined for tumor growth, length of survival and the presence of regional nodal and distant metastases. Conversely, we will demonstrate the anoikis resistance of cell lines that we have derived from in vivo orthotopic selection of regional and distant metastases by quantitation of their survival in suspension culture. The second hypothesis guiding the next Aim of this application is that the pro-survival signals mediating anoikis resistance are not constitutive but rather are induced by the process of cell detachment data to date, suggest that this is due to the induction of apoptosis suppression that is far downstream, as we have found that cell detachment induces resistance to multiple forms of apoptosis induction by both the extrinsic and intrinsic pathways. The third hypothesis is that the BiR containing proteins c-IAP-2, survivin, and XIAP are mediating the detachment-induced survival in the face of multiple forms of apoptotic signaling. This hypothesis will be tested by increasing and decreasing expression or activity of either of these two regulatory molecules in5cell lines and examining the resultant cell lines for their anoikis resistance in vitro and their tumorigenicity and metastatic potential in vivo. The final hypothesis is that expression of the downstream apoptotic regulatory molecules c-IAP-2, survivin, and XIAP is associated with tumor progression and metastasis in human SCCOC and in an orthotopic model of oral cancer. To demonstrate that these apoptotic regulatory molecules are expressed in human SCCOT tumors and that their expression is linked with poorer clinic pathologic outcomes, archival human SCCOT tumor will be evaluated for expression of these apoptotic regulatory molecules by in situ hybridization and immunhistochemistry. It is anticipated that high expression of apoptotic inhibitory molecules in tumor specimens from patients with poor clinicopathologic outcomes will provide insight into the potential roles of the IAPsas prognostic indicators and/or therapeutic targets. Further support for these roles of IAPs will result from demonstration that increased expression of these molecules leads to more aggressive tumor growth and metastasis in an orthotopic metastatic model of SCCOT.

描述（由申请人提供）：目前肿瘤进展的理论假设正常上皮细胞需要获得逃避凋亡的机制并获得其他几种基本生物学特性，以便进展为侵袭性和转移性肿瘤。从基底膜脱离后的程序性细胞死亡被称为oikis。该应用的中心假设是，逃避失巢凋亡与口腔鳞状细胞癌（SCCOC）的局部肿瘤进展和转移相关。将在四个单独的目标中评价四个单独的相互关联的假设。第一个假设是失巢凋亡抗性对于肿瘤进展是必要的，但不是充分的，包括局部生长以及区域和远处转移。为了证明失巢凋亡抗性与疾病进展相关，我们将研究人SCCOC细胞系在我们开发的原位裸鼠模型中的生长。将在体外选择的人SCCOC细胞系和抗失巢凋亡细胞注射到裸鼠的舌中，并检查这些小鼠的肿瘤生长、存活时间以及区域淋巴结和远处转移的存在。相反，我们将证明失巢凋亡抗性的细胞系，我们已经从体内原位选择的区域和远处转移，通过定量他们的生存在悬浮培养。指导本申请的下一个目的的第二个假设是，介导失巢凋亡抗性的促存活信号不是组成性的，而是由迄今为止的细胞脱离数据的过程诱导的，表明这是由于诱导了远下游的凋亡抑制，因为我们已经发现细胞脱离诱导了对通过外源性和内源性途径诱导的多种形式的凋亡诱导的抗性。第三个假设是，在面对多种形式的凋亡信号传导时，含有BiR的蛋白质c-IAP-2、存活素和XIAP介导凋亡诱导的存活。这一假设将通过增加和减少这两种调节分子中的任一种在5个细胞系中的表达或活性来测试，并检查所得细胞系的体外失巢凋亡抗性和体内致瘤性和转移潜力。最后一个假设是下游凋亡调控分子c-IAP-2、生存素和XIAP的表达与人SCCOC和口腔癌原位模型中的肿瘤进展和转移相关。为了证明这些凋亡调节分子在人SCCOT肿瘤中表达，并且其表达与较差的临床病理结局相关，将通过原位杂交和免疫组织化学评价存档人SCCOT肿瘤中这些凋亡调节分子的表达。预期来自具有不良临床病理结果的患者的肿瘤标本中的凋亡抑制分子的高表达将提供对IAPs作为预后指标和/或治疗靶点的潜在作用的深入了解。对IAP这些作用的进一步支持将来自于这些分子的表达增加在SCCOT的原位转移模型中导致更具侵袭性的肿瘤生长和转移的证明。