Macrophage-driven progression of premalignant oral lesions toward invasiveness

描述（由申请人提供）：特定组的癌前口腔病变与发展为口腔鳞状细胞癌（OSCC）的高发率相关。增生异常的癌前病变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进展，我们假设口腔癌前病变内的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后，巨噬细胞获得了刺激癌前病变细胞运动和侵袭的能力。这种运动刺激主要是通过巨噬细胞产生TGF-¿1介导的。反过来，TGF- 1会降低丝氨酸/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。降低的PP-2A活性本身就足以激活运动刺激通路。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，抑制PP-2A通过需要paxillin丝氨酸磷酸化及其与FAK/Src/paxillin局灶黏附复合物分离的途径刺激运动。在pp - 2a抑制细胞的运动刺激中还需要Src的激活、PI3K信号拮抗剂PTEN的失活和PI3K活性。本研究的假设是巨噬细胞来源的TGF-¿1驱动癌前病变细胞向侵袭性发展，阻断运动信号通路阻断恶性进展。这一假设将通过以下具体目的进行检验：1。定义巨噬细胞来源的TGF-¿1如何触发癌前病变细胞的运动性。2. 在体内证明巨噬细胞在驱动癌前病变细胞侵袭中的作用。方法：本研究将通过患者样本和致癌物诱导的癌前病变小鼠模型来确定巨噬细胞来源的TGF-¿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-¿R/Smad信号。意义：这些研究将明确巨噬细胞如何参与高危口腔癌前病变细胞的侵袭。此外，它们将为预防具有恶性进展高风险的癌前口腔病变患者的OSCC的新方法提供基础。公共卫生相关性：口腔鳞状细胞癌是世界上第六大最常见的肿瘤，5年生存率低于50%。所提出的研究与减少口腔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.