The tumorigenic potential of tumor adjacent histologically normal breast tissue.

邻近组织学正常乳腺组织的肿瘤的致瘤潜力。

基本信息

批准号：
8540404
负责人：
Kristina Antonia Trujillo
金额：
$ 15.44万
依托单位：
UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-05 至 2015-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8540404
关键词：
Adjuvant Agar Alleles Antibodies Breast Breast-Conserving Surgery CDKN2A gene Cell Proliferation Cells Characteristics Coculture Techniques Conditioned Culture Media Data Dependency Enzyme-Linked Immunosorbent Assay Epithelial Epithelial Cells Epithelium Evaluation Exhibits Fibroblasts Genomics Goals Growth Histologic Human In Vitro Investigation Large T Antigen Malignant Neoplasms Mammary Gland Parenchyma Mammary Neoplasms Mammary gland Measures Messenger RNA Mitogens Molecular Molecular Abnormality Normal tissue morphology Oncogene Proteins Oncogenic Operative Surgical Procedures Patients Phenotype Population Property Public Health Radiation therapy Recurrence Residual Cancers Signal Transduction Simian virus 40 Small Interfering RNA Stromal Cell-Derived Factor 1 Surgical margins Testing Tissues Transcript Tumor Tissue Tumorigenicity Woman Wound Healing breast lumpectomy cancer cell cell transformation cytokine immortalized cell knock-down malignant breast neoplasm migration research study telomerase reverse transcriptase tissue culture tumor tumorigenesis tumorigenic

项目摘要

DESCRIPTION (provided by applicant): Seven-15% of women who undergo breast conservation surgery have local recurrences, despite seemingly adequate surgical margins, consolidation with radiation therapy and adjuvant systemic therapies1. This is thought to be caused by residual cancer cells outside the surgical margin2-4. In contrast, we have shown that the cells in histologically normal tissue up to 1 cm away from breast tumors have several molecular alterations that suggest they may also contribute to local recurrence. The epithelial populations demonstrate genomic instability5, and a mechanism for immortalization6-7 (hTERT expression levels similar to those found in tumors). Furthermore, the fibroblasts within these tissues exhibit wound healing properties, which is a characteristic of Cancer Associated Fibroblasts8 (CAFs) and known to promote tumorigenesis9. We term tumor adjacent tissue with these abnormal characteristics Field Cancerized Tissue (FCT). Since an adequate surgical margin for a lumpectomy is defined as 2 mm, and FCT tissue extends at least 1 cm from the margin, FCT often remains in a woman after breast conserving surgery. However, it is not known if the cells within this tissue are pre- disposed to tumorigenesis, and thus contribute to local recurrence. Our long-term goal is to understand if the molecular alterations in FCT are a cause of local recurrence. The objective of this proposal is to understand the tumorigenic potential of cells within FCT in vitro. Our central hypothesis is that the molecular abnormalities n both epithelial and fibroblast cells from FCT confer tumorigenic properties. Aim 1 will determine if epithelial cells from FCT exhibit tumorigenic properties known to be conferred by hTERT. hTERT confers mitogen independence and immortalize cells and, in combination with other oncoproteins, tumorigenically transforms cells. We hypothesize that TAHN-1 epithelial cells also share these properties. Aim 2 will compare SDF-1 and TGF-¿ signaling between fibroblasts in FCT and CAFs. CAFs secrete SDF-1 and TGF¿, which function to auto-stimulate their own proliferation along with that of adjacent epithelial cells. We predict that TAHN-1 fibroblasts also secrete these cytokines, and that their observed autostimulatory growth is dependent on these cytokines. Aim 3 will assess the tumorigenic potential of co-mixed epithelial cells and fibroblasts from FCT in vitro. CAFs cause the progression of initiated (i.e., expressing SV40 Large T- antigen) non-tumorigenic epithelial cells in vitro and in vivo9; however, CAFs do not cause progression of non-initiated cells9. We anticipate that CAFs will stimulate progression of TAHN-1 epithelial cells; and that TAHN-1 fibroblasts will stimulate progression of initiated and TAHN-1 epithelial cells. We will also test if TAHN-1 fibroblasts can stimulate progression of TAHN-1 epithelial cells. The proposed investigations will provide the first evaluation of the tumorigenic potential of the histologically normal tissue that often remains after breast conserving surgery. This proposal challenges the assumption that local recurrence is always due to residual cancer cells and, therefore, has implications on the adequacy of current standards for surgical margins in breast cancer.

描述（由申请人提供）：尽管手术切缘看似足够，并经过放射治疗和辅助全身治疗进行巩固，但接受保乳手术的女性中有 7-15% 会出现局部复发，这被认为是由手术外残留的癌细胞引起的。相比之下，我们发现距离乳腺肿瘤 1 厘米的组织学正常组织中的细胞有一些分子改变，表明它们也可能导致局部复发。以及永生化机制6-7（hTERT 表达水平与肿瘤中相似）此外，这些组织内的成纤维细胞表现出伤口愈合特性，这是癌症相关成纤维细胞8 (CAF) 的特征，并且已知可促进邻近肿瘤的发生9。具有这些异常特征的组织现场癌化组织 (FCT) 由于肿瘤切除术的足够手术边缘定义为 2 毫米，并且 FCT 组织从边缘延伸至少 1 厘米，因此 FCT 经常。然而，尚不清楚该组织内的细胞是否易于发生肿瘤，从而导致局部复发。我们的长期目标是了解 FCT 中的分子改变是否会导致局部复发。该提案的目的是了解 FCT 中细胞的体外致瘤潜力，我们的中心假设是 FCT 中的上皮细胞和成纤维细胞的分子异常会赋予目标 1 致瘤特性。确定来自 FCT 的上皮细胞是否表现出已知由 hTERT 赋予的致瘤特性。hTERT 赋予细胞分裂原独立性并使细胞永生化，并且与其他癌蛋白结合，致瘤转化细胞也具有这些特性。将比较 SDF-1 和 TGF-¿ FCT 和 CAF 中成纤维细胞之间的信号传导分泌 SDF-1 和 TGF¿ ，其功能是自动刺激自身增殖以及邻近上皮细胞的增殖，我们预测 TAHN-1 成纤维细胞也能。分泌这些细胞因子，并且它们观察到的自刺激生长依赖于这些细胞因子。目标 3 将评估共混合上皮细胞和成纤维细胞的致瘤潜力。来自 FCT 的体外和体内 CAF 会导致起始（即表达 SV40 大 T 抗原）非致瘤性上皮细胞的进展；然而，CAF 不会导致非起始细胞的进展 9。刺激 TAHN-1 上皮细胞的进展；并且 TAHN-1 成纤维细胞将刺激起始的 TAHN-1 上皮细胞的进展。还测试 TAHN-1 成纤维细胞是否可以刺激 TAHN-1 上皮细胞的进展。拟议的研究将对保乳手术后通常残留的组织学正常组织的致瘤潜力进行首次评估。总是由于残留癌细胞所致，因此对乳腺癌手术切缘现行标准的充分性产生影响。