Mechanism regulating ErbB signaling network in head and neck cancer

描述（申请人提供）：浸润性鳞状细胞癌是上消化道最常见的恶性肿瘤。尽管手术和放射治疗方法取得了进展，但口腔和头颈癌的总体预后仍然很差，主要原因是其侵袭性、复发性以及局部和远处转移。伴有局部转移的口腔鳞状细胞癌生存率接近50%。迫切需要开发新的分子靶点，从而产生新的有效的治疗方法。鳞状细胞癌表现为紧密相关的三维肿瘤巢，具有广泛的细胞-细胞连接粘连，允许细胞生长和抵抗凋亡损伤。我们的发现暗示了细胞间粘附参与了这种保护，并揭示了细胞间接触提供了离散的细胞存活信号。该项目的总体目标是确定调节生长因子受体信号谱的机制，这些信号谱导致更具侵袭性的口腔SCC细胞群，并确定复杂的细胞微环境相互关系如何促进对靶向ErbB轴家族成员的抑制剂的耐药性发展。最近的临床研究已经检查了在HNSCC中ErbB3过表达的预后相关性，并报告了ErbB3升高与转移性疾病和较差的患者总体生存率相关。本项目特别关注在口腔SCC发展中，肿瘤细胞高密度三维巢促进特定ErbB家族信号谱的转变，有利于增强增殖和肿瘤进展的最重要假设。目的1将研究3d肿瘤微环境如何调节细胞生长。目的2将确定控制肿瘤灶中ErbB受体谱的机制。目的3将明确HIF-1α诱导ErbB受体表达在肿瘤进展中的重要性。这些拟议的研究应该促进对侵袭性HNSCC进化的更多理解，可以用于未来开发新的治疗策略。

DESCRIPTION (provided by applicant): Invasive squamous cell carcinoma is the most common malignant tumor of the upper aerodigestive tract. Despite advances in surgical and radiotherapeutic approaches for therapy, the overall prognosis of oral and head and neck cancer remains poor primarily due to its aggressive invasive capacity, recurrence, and local and distant metastases. Oral squamous cell carcinomas with regional metastasis have a survival rate close to 50%. There is an urgent need to develop novel molecular targets that yield new effective therapeutic approaches. Squamous cell carcinomas present as tightly associated nests of three-dimensional tumor with extensive cell-cell junctional adhesions that permit cell growth and resistance to apoptotic insults. Our findings implicated the involvement of intercellular adhesions in conferring this protection and revealed that cell-cell contacts provide discrete cell survival signaling. The overall goal of this project is to define the mechanisms that regulate growth factor receptor signaling profiles that lead to more aggressive oral SCC cell populations and to identify how complex cellular microenvironmental interrelationships contribute to development of resistance to inhibitors targeting ErbB axis family members. Recent clinical studies have examined the prognostic relevance of overexpressed ErbB3 in HNSCC and report that elevated ErbB3 correlates with metastatic disease and poor overall patient survival. This project focuses specifically on the overriding hypothesis that in oral SCC development, high-density three-dimensional nests of tumor cells promote shifts in specific ErbB family signaling profiles favoring enhanced proliferation and tumor progression. Aim 1 will investigate how the 3D-tumor microenvironment regulates cell growth. Aim 2 will identify the mechanism controlling ErbB receptor profile in tumor foci. Aim 3 will define the importance of HIF-1α induction of ErbB receptor expression in tumor progression. These proposed studies should foster an increased understanding of the evolution of aggressive HNSCC that could be exploited for the future development of novel therapeutic strategies.