Understanding the effect of aging on cancer incidence

了解衰老对癌症发病率的影响

• 批准号: 10043596
• 负责人: Maria Lucia Gomez
• 金额: $ 7.68万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2020-11-03
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10043596
• 关键词: 3-Dimensional; Address; Affect; Age; Aging; Architecture; Biological; Biological Aging; Breast; Breast Cancer Model; Breast Cancer Patient; Breast Cancer Risk Factor; Breast Cancer Treatment; Breast Epithelial Cells; Cancer Biology; Cell Differentiation process; Cells; Collagen; Collagen Fiber; Confocal Microscopy; Data; Development; Diagnosis; Disease; Down-Regulation; ERBB2 gene; Elderly; Elderly woman; Environment; Epigenetic Process; Experimental Models; Extracellular Matrix; Female; Fiber; Genetic; Goals; Growth; Human; Image; In Vitro; Incidence; Inflammation; Lead; Link; Malignant Neoplasms; Mammary Neoplasms; Mammary Tumorigenesis; Mammary gland; Methods; Modeling; Molecular; Mouse Mammary Tumor Virus; Mus; Oncogenes; Oncogenic; Pathway interactions; Patient-Focused Outcomes; Play; Population; Process; Rattus; Research Personnel; Resolution; Risk; Risk Factors; Role; Sample Size; Series; Structure; Tail; Testing; Training; Transgenic Mice; Trichrome stain; Woman; Work; Xenograft procedure; age effect; age related; aged; aging population; base; breast cancer diagnosis; career; cell behavior; cell growth; cohort; experimental study; genetic signature; improved; in vivo; in vivo Model; in vivo imaging; insight; malignant breast neoplasm; matrigel; mouse genetics; mouse model; neoplastic cell; next generation sequencing; novel; older patient; older women; scaffold; second harmonic generation imaging; three dimensional cell culture; transcriptome; transcriptome sequencing; tumor; tumor growth; tumorigenesis

PROJECT SUMMARY In breast cancer, the median age of diagnose is 61 year old and the incidence then declines in elderly women. However, very few studies focus on the effect of age-related changes on tumorigenesis in the aged breast and almost all experimental models use young mice (3 months). Therefore there is a need to develop mouse models that best reflect the incidence of the disease in humans using aged rather than young or elderly mice. In order to begin characterizing the effect of aging in mammary tumorigenesis, we performed preliminary studies in an inducible mammary tumor model, in which all variables are identical except for age. After oncogene induction, we found that aged (18 months = 61 years in humans) mice have increased tumor incidence, compared to young (3 months) mice. In addition, tumors from aged mice express a unique genetic signature, compared to tumors from young mice. In contrast the increased tumor growth in vivo, aged mammary epithelial cells induced ex vivo formed smaller colonies compared to induced young mammary epithelial cells. Furthermore, our preliminary studies also suggest that the aged mammary gland is characterized by a decrease in collagen abundance and disorganized fiber orientation. Based on these findings, we propose to further analyze age-related alterations in both normal and tumor mammary cells, and microenvironment architecture (collagen abundance and orientation). In Aim 1, we will assess cell-intrinsic age-related changes in tumors arising from aged mice. We will perform transcriptome analysis of tumor cells arising from young and old females in two mouse mammary tumor models, MMTV-rtTA/TetO-ErbB2 and MMTV-rtTA/TetO-Ras. To identify potential novel targets in tumors arising from aged mice, we will compare the young and aged tumor signatures with young and old normal mammary epithelial cells. In Aim 2, we will investigate the cell-extrinsic effect of age-related changes in collagen composition on mammary tumor growth. First, we will further characterize the age-related changes in collagen abundance and orientation young and aged normal mammary glands using second harmonic generation imaging. We will also establish a 3D culture method using decellularized mammary glands from young and aged mice to study the effect of biological aging on tumor cell growth in vitro. We will confirm our studies in a series of swapping experiments using establish young and aged syngeneic cohorts. The purpose of the proposed studies is to improve our understanding of how age-related changes in the mammary gland contribute to breast cancer risk, and may identify new targets for breast cancer treatment in older women.

项目摘要 在乳腺癌中，诊断年龄的中位年龄为61岁，而老年妇女的发病率下降。 但是，很少有研究重点是年龄相关变化对老年乳房肿瘤发生的影响， 几乎所有实验模型都使用年轻小鼠（3个月）。因此需要开发鼠标 最能使用年龄而不是年轻小鼠或老年小鼠反映人类疾病发生率的模型。 为了开始表征乳腺肿瘤发生衰老的作用，我们进行了初步 在可诱导的乳腺肿瘤模型中的研究，其中所有变量除了年龄外，所有变量都是相同的。后 癌基因诱导，我们发现年龄（18个月= 61岁）的小鼠增加了肿瘤 与年轻小鼠相比，发病率。此外，来自老年小鼠的肿瘤表达了独特的遗传 与年轻小鼠的肿瘤相比，签名。相反，体内肿瘤生长增加，年龄 与诱导的年轻乳腺相比 上皮细胞。此外，我们的初步研究还表明，老化的乳腺是 其特征是胶原蛋白丰度降低和纤维方向混乱。基于这些 调查结果，我们建议进一步分析正常和肿瘤乳腺细胞中与年龄相关的改变，以及 微环境建筑（胶原蛋白丰富和方向）。在AIM 1中，我们将评估细胞内在 老年小鼠引起的肿瘤与年龄相关的变化。我们将对肿瘤细胞进行转录组分析 在两个小鼠乳腺肿瘤模型中，由年轻和老年女性产生，MMTV-RTTA/TETO-ERBB2和 MMTV-RTTA/TETO-RAS。为了确定由老年小鼠引起的肿瘤中潜在的新靶标的，我们将比较 年轻和老化的肿瘤特征与年轻和老式的正常乳腺上皮细胞。在AIM 2中，我们将 研究胶原蛋白组成对乳腺肿瘤生长的年龄相关变化的细胞肢体影响。 首先，我们将进一步描述与年龄相关的胶原蛋白丰度和取向年轻的变化， 使用第二个谐波产生成像的老年正常乳腺。我们还将建立3D文化 方法使用来自年轻小鼠和老年小鼠的脱细胞乳腺来研究生物衰老的作用 在体外肿瘤细胞生长上。我们将使用建立的一系列交换实验确认我们的研究 年轻和老年人同类人群。拟议研究的目的是提高我们对 乳腺与年龄相关的变化如何导致乳腺癌风险，并可能确定新目标 用于老年妇女的乳腺癌治疗。