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。

• 批准号: 8388685
• 负责人: Kristina Antonia Trujillo
• 金额: $ 19.71万
• 依托单位: UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-05 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8388685
• 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

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. PUBLIC HEALTH RELEVANCE: We have shown that the histologically normal tissue up to 1 cm away from breast tumors has molecular changes that may pre-dispose this tissue for tumor formation. This relates to public health because adequate surgical margins can be as little as 2 mm, therefore this tissue likely remains in many women following breast conserving surgery. Our long-term goal is to understand if the molecular alterations in this tissue are a cause of loca recurrence. The objective of this proposal is to understand the potential of cells within this tisse to become cancer cells in tissue culture.

描述（由适用提供）：尽管手术边缘似乎足够，接受乳房保存手术的妇女中有7％的妇女仍获得局部回报，但与放射治疗合并并调整了全身疗法1。这被认为是由手术边缘以外的残留癌细胞引起的。2-4。相比之下，我们已经表明，远离乳腺肿瘤1 cm的组织学正常组织中的细胞具有多种分子改变，这表明它们也可能有助于局部复发。上皮种群表明基因组不稳定性5和永生化的机制6-7（HTERT表达水平与肿瘤中发现的水平相似）。此外，这些尖端中的成纤维细胞暴露了伤口愈合特性，这是癌症相关成纤维细胞8（CAF）的特征，并已知促进肿瘤衰变9。我们以这些异常特征癌症组织（FCT）为邻近组织。由于肿块切除术的足够手术边缘定义为2 mM，FCT组织从边缘至少延伸1 cm，因此在乳房保存手术后，FCT通常保留在女性中。但是，尚不清楚该组织中的细胞是否预先鉴定为肿瘤发生，因此有助于局部复发。我们的长期目标是了解FCT的分子改变是否是局部复发的原因。该提案的目的是了解FCT体外FCT中细胞的肿瘤潜力。我们的中心假设是，来自FCT会议肿瘤特性的上皮细胞和成纤维细胞的分子异常。 AIM 1将确定来自HTERT赋予的FCT暴露肿瘤特性中的上皮细胞。 HTERT赋予有丝分裂原独立性并使细胞永生，并与其他癌蛋白结合使用，可转化细胞。我们假设TAHN-1上皮细胞也具有这些特性。 AIM 2将比较FCT和CAF中成纤维细胞之间的SDF-1和TGF- - 信号传导。 CAFS Secret SDF-1和TGF¿，它们与相邻的上皮细胞一起自动刺激自己的增殖。我们预测TAHN-1成纤维细胞也 分泌这些细胞因子，并且它们观察到的自刺激生长取决于这些细胞因子。 AIM 3将评估共粘的上皮细胞和成纤维细胞的破坏性潜力 来自FCT体外。 CAF会导致启动（即表达SV40大型T-抗原）非肿瘤上皮细胞在体外和vivo9的进展；但是，CAF不会引起非发射细胞的进展9。我们预计CAF会刺激TAHN-1上皮细胞的进展。 TAHN-1成纤维细胞将刺激启动和TAHN-1上皮细胞的进展。我们还将测试TAHN-1成纤维细胞是否可以刺激TAHN-1上皮细胞的进展。拟议的研究将对组织学正常组织的致瘤潜力进行首次评估，该组织经常在乳房保存手术后保留。该提议挑战了以下假设：局部复发始终是由于残留的癌细胞引起的，因此对乳腺癌手术边缘的当前标准足够有影响。 公共卫生相关性：我们已经表明，远离乳腺肿瘤1 cm的组织学正常组织具有分子变化，可能会预先介绍该组织以形成肿瘤。这与公共卫生有关，因为足够的手术边缘可能只有2毫米，因此在乳房保存手术后，这种组织可能仍然保留在许多女性中。我们的长期目标是了解该组织中的分子改变是否是局部复发的原因。该提案的目的是了解该TISSE中细胞在组织培养中成为癌细胞的潜力。