Does stanniocalcin predict late breast cancer recurrence, or is it a fish story?

斯钙素是否能预测晚期乳腺癌复发，还是纯属虚构？

基本信息

批准号：
8692147
负责人：
Timothy L. Lash
金额：
$ 18.8万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-26 至 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8692147
关键词：
Adipocytes Adjuvant Therapy Affect Antineoplastic Agents Apoptosis Attention Biological Assay Biological Markers Biology Breast Cancer Detection Calcium Cancer Patient Cancer Prognosis Cancer Survivor Cardiac Myocytes Case-Control Studies Cell Death Cell division Cells Characteristics Climate Clinical Clinical Data Colorectal Cancer Development Diagnosis Disease Distant Effectiveness Endocrine Endocrine Glands Environment Equilibrium Face Fishes Gills Growth Hormones Human Hypoxia Immunologic Surveillance In Vitro Investments Kidney Lead Life Link Malignant Neoplasms Measures Micrometastasis Mind Mitochondria Molecular Neoplasm Metastasis Neurons Normal Cell Oocytes Osteichthyes Ovum Pathway interactions Patients Pharmaceutical Preparations Population Positioning Attribute Primary Neoplasm Process Protons Provider Radiation therapy Recruitment Activity Recurrence Research Support Risk STC1 gene STC2 gene Signal Transduction Solid Neoplasm Staging Stratification Stress Surface Theca folliculi structure Time Tissues Toxic effect analog assault biobank breast cancer diagnosis calcium phosphate cancer recurrence cancer site cancer therapy cell growth chemotherapy cohort follow-up glycosylation heart cell high reward high risk hormone therapy human STC1 protein improved inorganic phosphate interstitial malignant breast neoplasm molecular marker mortality neoplastic cell novel therapeutics paracrine prevent prognostic programs prophylactic public health relevance screening stanniocalcin 2 success teleocalcin trait tumor

项目摘要

PROJECT SUMMARY/ABSTRACT Advances in the effectiveness of breast cancer screening and treatment have reduced the breast cancer mortality rate over the last decades. These advances come from avoided recurrences, but also from delayed recurrences. The success of chemotherapy, endocrine therapy, and radiation therapy, is typically measured by a reduction in the risk of recurrence in the first five years after breast cancer diagnosis. Many recurrences, however, occur late; that is, more than five years after diagnosis. These recurrences erupt from single dormant cells or micro-metastases where tumor cell growth has been balanced by tumor cell death. How does a single cell, or a small colony of cells, survive for more than five years in a hostile microenvironment that, at least at the outset, often includes hypoxic climates induced by cancer therapies? One likely explanation is that tumors with the capability to recruit stanniocalcin are more likely to survive in this setting and to recur five or more years after diagnosis. Stanniocalcin is a hormone first discovered in bony fish, where it regulates the concentration of calcium at the gills. In humans, nerve cells, fat cells, heart cells, ova, and other long-lived cells recruit stanniocalcin as a survival strategy when they face hypoxic stress, helping them to live in sometimes harsh conditions by uncoupling proton transport from glycosylation in the mitochondria. Preliminary human evidence and in vitro studies show that tumor expression of stanniocalcin is a marker of recurrence risk, and particularly late recurrence risk. We propose, therefore, to use an existing biobank from ~1700 breast cancer patients (841 with recurrence and 841 matched controls) linked to complete clinical data and long-term follow-up for recurrence to investigate whether stanniocalcin expression is a specific marker for late recurrence risk. We will determine whether breast cancer patients with late recurrences were more likely to have had primary tumors that express stanniocalcin than breast cancer patients with early recurrences. We will also determine whether the tumor cells of those with late recurrence are more likely to have retained or acquired the ability to express stanniocalcin than the tumor cells of those with early recurrence. If we find that stanniocalcin is a specific marker for late breast cancer recurrence, we will seek new research support to validate the result in a second breast cancer cohort and in a colorectal cancer cohort, and to investigate drugs to disrupt the pathway. There is no specific marker for late recurrence risk. A marker that predicts when a recurrence will occur, rather than whether a recurrence will occur, would change the clinical paradigm for cancers with substantial late recurrence risk. It would allow personalization of recurrence screening strategies, development of low- toxicity prophylactic therapies that begin when the late recurrence risk rises, and personalization of existing adjuvant therapies with regard to time from diagnosis. This R21 high-risk, high-reward project will initiate a program to identify markers of late recurrence risk and strategies to reduce or ameliorate that risk.

项目概要/摘要乳腺癌筛查和治疗有效性的进步已经减少了乳房过去几十年的癌症死亡率。这些进步不仅来自避免复发，还来自延迟复发。化疗、内分泌治疗和放射治疗的成功通常取决于通过乳腺癌诊断后头五年内复发风险的降低来衡量。许多然而，复发发生得较晚；也就是说，诊断后五年多。这些复发是从单个休眠细胞或微转移，其中肿瘤细胞的生长已通过肿瘤细胞死亡来平衡。如何单个细胞或一小群细胞能否在恶劣的微环境中存活五年以上至少在一开始，通常包括癌症治疗引起的缺氧气候？一种可能的解释是，具有招募斯钙素能力的肿瘤更有可能存活在这种情况下，并且在诊断后五年或更长时间内复发。斯钙素是一种激素，最早发现于硬骨鱼，它调节鳃处钙的浓度。在人类中，神经细胞、脂肪细胞、心脏当细胞、卵子和其他长寿细胞面临缺氧应激时，它们会招募斯钙素作为生存策略，通过将质子运输与糖基化解偶联来帮助它们在有时恶劣的条件下生活线粒体。初步人体证据和体外研究表明，斯钙素的肿瘤表达是一种复发风险，特别是晚期复发风险的标志。因此，我们建议使用现有的来自约 1700 名乳腺癌患者（841 名复发患者和 841 名匹配对照者）的生物样本库与完整的乳腺癌相关临床数据和长期随访复发情况，以研究斯钙素表达是否是特异性的晚期复发风险的标记。我们将确定晚期复发的乳腺癌患者是否与早期患有乳腺癌的患者相比，他们更有可能患有表达斯钙素的原发肿瘤复发。我们还将确定晚期复发者的肿瘤细胞是否更有可能与早期癌症患者的肿瘤细胞相比，保留或获得了表达斯钙素的能力复发。如果我们发现斯钙素是晚期乳腺癌复发的特异性标志物，我们将寻求新的研究支持以验证第二个乳腺癌队列和结直肠癌队列的结果，以及研究破坏该途径的药物。没有针对晚期复发风险的特定标记。预测何时复发的标记，而不是是否会发生复发，将改变癌症的临床范式晚期复发风险。它将允许个性化复发筛查策略，开发低当晚期复发风险上升时开始毒性预防性治疗，以及现有的个体化治疗与诊断时间相关的辅助治疗。这个R21高风险、高回报的项目将启动确定晚期复发风险标记的计划以及减少或改善该风险的策略。