Plastic States Associated with Cellular Stress and Malignancy: Insights for Prevention and Treatment of Lethal Metaplastic Cancers

 描述（由申请人提供）：我们的长期目标是为一组癌症找到有效的预防和治疗方法，这些癌症是全球癌症死亡率的不成比例原因。该建议将寻求确定一组侵袭性恶性肿瘤的起源细胞，这些恶性肿瘤来自不同的部位，具有共同的病因学，即对慢性炎症的化生反应。我们以前的研究，以及他们所产生的新见解，为我们提供了一个令人信服的假设，违背了目前的教条和这些选定的恶性肿瘤的分类。我们建议，选择癌症的子集，在这个建议中的食管腺癌，胃癌的不确定类型和化生性乳腺癌的例子，产生于独特的表型可塑性细胞，赋予侵略性表型与极差的预后。这些癌的亚群以癌前病变和恶性病变中存在化生组织衍生物为代表。化生是一种保护性适应性组织反应，其中一种细胞类型被另一种通常不存在于该组织中的细胞类型所取代， 损伤，并与癌症发病率增加有关。解开这些“化生癌”的生物学将使我们能够克服识别诱发条件和随后激活导致致命化生癌的起源细胞的障碍，并开发生物标志物来识别那些将进展为浸润性癌症的癌前病变。识别和靶向控制这些细胞进展的信号通路将使我们能够设计针对这些癌的侵袭性状态的合理治疗方法。最后，我们还提出了一种新的预防方法，以减少形成的癌前状态，这些恶性肿瘤的基础。实现我们的目标将改变临床实践，并允许医生在这些癌症形成之前阻止它们。我们建议：（1）确定特定干/再生细胞在食管腺癌、不确定类型的胃癌和三阴性乳腺癌（即化生性乳腺癌）的亚组的起始和进展中的作用。我们还将（2）识别不同的分子特征（细胞状态），并将其与（3）靶向预防和（4）治疗的最佳方法相匹配。慢性炎症和恶性肿瘤之间的联系是众所周知的;然而，尽管了解因果关系，这些恶性肿瘤的发病率在现代世界中正在增加，并显着导致癌症死亡率。如果成功， 该提案的目标将描绘出一种治疗范例，可以降低这类癌症的死亡率，并从根本上改变我们预防癌症的方法。

 DESCRIPTION (provided by applicant): Our long-term goals are to find effective preventive and therapeutic approaches for a group of carcinomas that are disproportionately responsible for cancer mortality worldwide. This proposal will seek to identify the cell of origin for a group f aggressive malignancies from disparate sites that share a common etiology of a metaplastic response to chronic inflammation. Our previous studies, and the novel insights they have generated, provide us with a compelling hypothesis that defies the current dogma and classification of these selected malignancies. We propose that select subsets of carcinomas, exemplified in this proposal by esophageal adenocarcinoma, gastric carcinoma of the indeterminate type and metaplastic breast cancers, arise from unique phenotypically plastic cells that confer aggressive phenotypes with extremely poor prognosis. These subsets of carcinomas are typified by the presence of metaplastic tissue derivatives in the pre-malignant and malignant lesions. Metaplasia, a protective adaptive tissue response where one cell type is replaced by another cell type not typically present in that tissue, is indicative of chronic tissue injury and associated with increased incidence of cancer. Unraveling the biology of these "metaplastic carcinomas" will allow us to overcome barriers to the identification of predisposing conditions and the subsequent activation of the cells-of-origin leading to lethal metaplastic carcinomas and to develop biomarkers to identify those premalignant lesions that will progress to invasive cancer. Identification and targeting of signaling pathways that control progression of these cells would allow us to design rational therapeutics that target the invasive state of these carcinomas. Finally, we also propose a novel preventive approach to reduce formation of the pre-malignant state that underlies these malignancies. Realization of our goals would change clinical practice and allow physicians to halt these cancers before they form. We propose to: (1) determine the role of specific stem/regenerative cells in initiation and progression esophageal adenocarcinomas, gastric cancers of indeterminate type and a subset of triple negative breast cancers, i.e. metaplastic breast cancers. We will also (2) identify distinct molecular features (cellular states) and match them with an optimal approach for (3) targeted prevention and (4) therapy. The connection between chronic inflammation and malignancy is well known; however despite an understanding of the causal insults, the incidences of these malignancies are increasing in the modern world and significantly contribute to cancer mortality. If successful, the goals of this proposal would delineate a therapeutic paradigm that could reduce mortality from this subset of cancers and fundamentally alter our approach to cancer prevention.