2009 |
Brown, Edward Bernard |
DP2Activity Code Description: To support highly innovative research projects by new investigators in all areas of biomedical and behavioral research. |
Exploiting Collagen Organization to Predict and Prevent Tumor Metastasis @ University of Rochester
DESCRIPTION (Provided by the applicant) Abstract: The extent and nature of the ordering of collagen fibers within a tumor has significant influence on metastasis: in murine breast tumor models, tumor cells move towards blood vessels along fibers that are visible via second harmonic generation (SHG), and SHG is exquisitely sensitive to molecular ordering. Tumor cells that move along SHG fibers are significantly faster than those moving independently, and SHGassociated motility is correlated with metastatic ability. Furthermore, the tumor-host interface contains radially oriented SHG fibers associated with tumor cells invading the surrounding tissue. Lastly, we have shown that treatment of tumors with relaxin, known to alter metastatic ability, alters collagen ordering as detectable by SHG. Consequently, we believe that the process of establishing ordered fibers offers an exciting, and currently unexploited, therapeutic target. To take advantage of this, we must first learn the cellular players and molecular signals by which collagen ordering is induced. Therefore, in this application we propose to determine the key cells and signals which influence the ordering of collagen in breast tumors. The tumor draining lymph node is the first bridgehead for many metastasizing tumor cells and we have exciting preliminary data suggesting that changes in collagen ordering within the node are evident (via SHG) before clinical detection of metastatic cancer, therefore we will also determine the key cells and signals which influence the ordering of collagen in the draining lymph node. Additionally, we will determine if SHG measures of collagen ordering in breast tumors and draining nodes are clinically useful predictors of metastatic outcome in breast cancer patient biopsies. This project has a high impact because it has two independent pathways to clinical relevance, by developing promising antimetastatic drug targets, and by developing an optical method to predict metastatic ability. Public Health Relevance: This project can positively impact public health in several ways. One part of the project is a determination of the cells and signals responsible for ordering collagen in breast tumors, and the resultant effects on metastasis. This will lead to target molecules for therapeutic intervention with the goal of inhibiting breast tumor metastasis. A second part of the project is an evaluation of the ability of optical measures of collagen ordering to predict metastatic ability. This will lead to an improvement in quality of life for breast cancer patients as therapy is customized to patient need.
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2016 — 2017 |
Brown, Edward Bernard Zhang, Xinping [⬀] |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Understanding Revascularization and Repair of Cranial Bone Grafts Via Intravital Imaging @ University of Rochester
Revascularization is a key determining factor in bone graft healing and repair. Autografts are vastly superior to allografts and synthetic bone grafts largely due to the fact that autografts can be rapidly revascularized and form new bone whereas allografts cannot. While vascularization of bone tissue has been increasingly recognized as a key factor in repair and reconstruction, our understanding of bone graft vascularization in bone transplantation has been limited to histological observations described in the early 70s and 80s. These descriptions are often restricted by dependency on histology which prohibits three-dimensional and spatiotemporal analyses of vascularization of the grafted bone. We have recently established a cranial bone window chamber model which allows high resolution, four-dimensional imaging and analyses of bone defect healing over a period of months using multiphoton laser scanning microscopy (MPLSM). By transplanting allograft and autograft bone into this windowed bone defect model, we were able to track the revascularization process and demonstrate the fundamental differences between allografts and autografts in living animals. The goal of our current proposal is to utilize this novel intravital imaging approach combined with transgenic animal models to gain a better understanding of the vascularization mechanisms of bone graft transplantation. Based on our preliminary date and recent literature on the key role of hypoxia-inducible factor 1- alpha (HIF-1?) in oxygen sensing and coupling of osteogenesis and angiogenesis, two complementary Aims are proposed. Aim 1 will examine the key role of the HIF-1 pathway in revascularization and repair by transplantation of a HIF-1 deficient or over-activated live bone isograft into a cranial defect window chamber model. Aim 2 will determine the effects of engraftment of MSCs with enhanced HIF-1 signaling on bone allograft revascularization and repair. A novel oxygen sensor, which allows quantitative measurements of oxygen tension simultaneously with osteogenesis and angiogenesis in vivo will be established. The completion of our current project will enhance our knowledge of graft healing and revascularization and further offer rationales and strategies to augment the efficacy of future cell-based therapy aimed at enhancing bone repair and regeneration. Understanding the complex role of hypoxia and its master regulators in bone graft revascularization and bone healing will further aid in the development of novel pharmaceutical agents that can redress the detrimental outcomes often seen in repair and scarring of bone allograft healing.
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2017 — 2018 |
Brown, Edward Bernard |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Using Second Harmonic Generation to Predict Metastatic Outcome in Colon Adenocarcinoma @ University of Rochester
When treating a colon adenocarcinoma (CA) patient, after surgical resection of the tumor the clinician must formulate a plan for adjuvant systemic therapy. This decision is based upon an assessment of the risk of systemic disease recurrence, and is currently informed by pathological factors such as stage, histological grade, and lymph node status. Improvement of the accuracy of risk assessment for individual patients is an area of recognized need. Much of the current information used to assess risk focuses on the cells within tumors, including their morphological properties. Less attention is paid to the extracellular matrix through which metastasizing cells must travel. Second harmonic generation (SHG) is an optical scattering phenomenon whose directionality (as quantified by the ?F/B? ratio) is affected by the diameter, spacing, and disorder of fibrils within collagen fibers. Our preliminary data suggests that F/B analysis of tumor samples provides prognostic information about future metastasis that is ?matrix-focused? and hence complementary to current ?cell-focused? methods. In a preliminary study in 44 Stage I colon adenocarcinoma samples we found that F/B of the primary tumor is a significant prognostic indicator of progression free survival time. Significantly, the quartile of Stage I patients with the lowest F/B ratio had a clinical outcome indistinguishable from Stage III patients: a 15 year progression free survival percentage of below 50%. In other words, in this study F/B identified a subset of Stage I patients who had survival statistics similar to Stage III patients. Stage I patients are rarely prescribed adjuvant chemotherapy while Stage III patients are almost always prescribed it. This suggests that F/B might be able to identify individual patients who would benefit from adjuvant chemotherapy and who would be left untreated based upon current prognostic indicators. The prognostic trend was also evident in a cohort of 72 Stage II colon adenocarcinoma samples, although it was not significant. Consequently we hypothesize that F/B is a clinically useful predictor of metastatic outcome in colon adenocarcinoma. This project will move this idea closer to the clinic by first (Aim 1) using archived samples and follow up data in separate training and validation sets to develop and test predictive algorithms that include F/B, in addition to clinical and genomic information. Second it will (Aim 2) quantify the effect of adjuvant chemotherapy on the predictive ability of the algorithms, as well as quantify their ability to predict chemotherapeutic efficacy. We predict that F/B analysis will be an effective tool that can reach the clinic rapidly after this study to improve metastatic risk assessment. Improving the accuracy of risk estimation for an individual patient will allow clinicians to treat those patients who are destined for metastases, improving outcomes, while avoiding treatment for those patients who are not, reducing overtreatment.!
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