Macrophage-driven progression of premalignant oral lesions toward invasiveness

描述（由申请人提供）：选定的口腔癌前病变组与发展为口腔鳞状细胞癌（OSCC）的高发病率相关。 癌前病变与异型增生水平增加含有较高的巨噬细胞含量。 由于肿瘤相关的巨噬细胞可以促进肿瘤的进展，我们假设，在癌前病变的口腔巨噬细胞也可以促进癌前病变细胞的运动性和侵袭性。 我们的初步研究表明，在暴露于癌前病变细胞，巨噬细胞获得的能力，刺激癌前病变细胞的运动和侵袭。 这种运动性的刺激主要通过巨噬细胞产生TGF-β 1介导。 反过来，TGF-β 1降低丝氨酸/苏氨酸蛋白磷酸酶PP-2A的活性及其激活剂神经酰胺的水平。 PP-2A活性降低单独足以激活运动刺激途径。 对角质形成细胞、癌前病变细胞和肿瘤细胞的初步研究表明，PP-2A的抑制通过需要桩蛋白的丝氨酸磷酸化及其从FAK/Src/桩蛋白粘着斑复合物解离的途径刺激运动性。 PP-2A抑制细胞的刺激运动性还需要Src的激活、PI 3 K信号传导拮抗剂PTEN的失活和PI 3 K活性。 本研究的假设是巨噬细胞来源的TGF-β 1驱动癌前病变细胞向侵袭性发展，并且中断运动信号通路阻断向恶性发展。 这一假设将通过以下具体目标进行检验：1。确定巨噬细胞源性TGF-β 1如何触发癌前病变细胞的运动。 2.在体内证实巨噬细胞在驱使癌前病变细胞侵袭中的作用。 方法：拟议的研究将确定患者样本和致癌物诱导的癌前病变小鼠模型中巨噬细胞衍生的TGF-β 1在刺激癌前病变细胞侵袭中的作用，以及这是否依赖于TGF-β R/Smad信号传导。 意义：这些研究将明确巨噬细胞如何促进高危癌前口腔病变细胞的侵袭。 此外，他们将提供新的方法，以防止口腔鳞状细胞癌的患者有癌前病变具有高风险的进展为恶性肿瘤的基础。 公共卫生相关性：口腔鳞状细胞癌是世界上第6大常见肿瘤，5年生存率低于50%。 拟议的研究与减少口腔癌从癌前病变发展为口腔癌的目标直接相关。

DESCRIPTION (provided by applicant): Select groups of premalignant oral lesions are associated with a high incidence of developing into oral squamous cell carcinoma (OSCC). Premalignant lesions with increased levels of dysplasia contain higher macrophage content. Since tumor-associated macrophages can facilitate tumor progression, we hypothesize that macrophages within premalignant oral lesions can also promote motility and invasiveness of premalignant lesion cells. Our pilot studies showed that upon exposure to premalignant lesion cells, macrophages acquire the capacity to stimulate the motility and invasiveness of premalignant lesion cells. This stimulation of motility is primarily mediated through macrophage production of TGF-¿1. TGF-¿1, in turn, diminishes the activity of the serine/threonine protein phosphatase, PP-2A, and levels of its activator, ceramide. Diminished PP-2A activity is alone sufficient to activate motility-stimulatory pathways. Pilot studies with keratinocytes, premalignant lesion cells and tumor cells have shown that inhibition of PP-2A stimulates motility through pathways that require serine phosphorylation of paxillin and its dissociation from FAK/Src/paxillin focal adhesion complexes. Also required in the stimulated motility of PP-2A-inhibited cells is activation of Src, inactivation of the PI3K signaling antagonist PTEN, and PI3K activity. The hypothesis of this study is that macrophage-derived TGF-¿1 drives premalignant lesion cells toward invasiveness and that interrupting the motility signaling pathways blocks progression toward malignancy. This hypothesis will be tested through the following specific aims: 1. To define how macrophage-derived TGF-¿1 triggers motility in premalignant lesion cells. 2. To demonstrate in vivo the role of macrophages in driving premalignant lesion cells toward invasiveness. Method: The proposed studies will define with patient samples and in carcinogen-induced premalignant lesion mouse models the role of macrophage-derived TGF-¿1 in stimulating invasiveness of premalignant lesion cells and if this is dependent on TGF-¿R/Smad signaling. Significance: These studies will define how macrophages contribute to the invasiveness of high-risk premalignant oral lesion cells. In addition, they will provide the foundation for new approaches by which to prevent OSCC in patients that have premalignant oral lesions having a high risk of progression to malignancy. PUBLIC HEALTH RELEVANCE: Oral squamous cell carcinoma is the 6th most common neoplasm in the world with a 5 year survival of less than 50%. The proposed studies have direct relevance to the goal of reducing oral cancer development from premalignant oral lesions.