MOLECULAR MECHANISMS OF TUMOR-INITIATED PREMETASTATIC NICHE FORMATION IN LUNG STR
S Randolph
Weill Medical College Of Cornell Univcity: New York country: United States (us)
Grant 5R01CA135417-03 from National Cancer Institute
Keywords: Angiogenesis Inhibitors; Animals; base; Biological Assay; Blood Circulation; Bone Marrow; Bone Marrow Cells; Bone Marrow Transplantation; cancer cell; Cancer Patient; Cause of Death; cell motility; Cells; cellular targeting; Clinical; Conditioned Culture Media; diphtheria toxin receptor; Disease; Disease Resistance; Endothelial Cells; Fibroblasts; Gene Targeting; Grant; Human; Immunocompetent; In Vitro; in vitro Assay; in vivo; ITGAM gene; Lung; lymph nodes; Maintenance; Malignant - descriptor; Malignant neoplasm of prostate; Malignant Neoplasms; Mammary Neoplasms; Maps; Mediating; Metastatic Neoplasm to the Lung; Metastatic to; Migration Assay; Modality; Modeling; Molecular; Mortality Vital Statistics; mouse model; Mus; mutant; Nature; Neoplasm Metastasis; neoplastic cell; neutralizing antibody; novel; Organ; Peripheral; Physiological; prevent; Primary Neoplasm; Principal Investigator; Proteins; public health relevance; Recruitment Activity; Relative (related person); Resistance; Role; Site; small hairpin RNA; Stromal Cells; Structure of parenchyma of lung; Tail; Therapeutic; Therapeutic Agents; therapeutic target; Thrombospondin 1; Time; Transgenic Mice; tumor; tumor xenograft; Tumor-Secreted Protein; Vascular Endothelial Growth Factor Receptor-1; Veins; Work; Xenograft Model
Relevance: Principal Investigators: Mittal, Vivek and Watnick, Randolph, S. The lungs are one of the most frequent sites of metastasis by human primary tumors, and lung metastasis is one of the leading causes of death in cancer patients due to the invasive nature of the disease and resistance to current treatment modalities. In this grant, we will elucidate molecular mechanisms by which prosaposin inhibits premetastatic niche formation and to identify the minimal active region of prosaposin, which may serve as the basis for novel anti-metastatic therapeutic agents. We will evaluate the therapeutic potential of prosaposin as well as cellular components of the niche as an approach to impair productive metastasis initiation and progression in physiological mouse models of pulmonary metastasis. Therapeutic targeting of metastasis initiation has tremendous promise for cancer patients who are likely to die of pulmonary metastasis
Project start date: 2010-02-01
Project end date: 2014-12-31
Budget start date: 1-JAN-2012
Budget end date: 31-DEC-2012
5R01CA135417-03 (2012): $450728
Sponsored Links Excellgen http://Excellgen.com
MOLECULAR MECHANISMS OF TUMOR-INITIATED PREMETASTATIC NICHE FORMATION IN LUNG STR
S Randolph, Director
Weill Medical College Of Cornell Univcity: New York country: United States (us)
Grant 5R01CA135417-02 from National Cancer Institute
Abstract: Lung metastasis is one of the leading causes of death in cancer patients, with a high mortality due to the invasive nature of the disease and its resistance to current treatment modalities. Despite the clinical importance, the cellular and molecular mechanisms that govern the initiation, establishment and progression of pulmonary metastasis remain unclear. However, more recent studies have begun to recognize the critical role of the local microenvironments in recruiting the disseminated malignant tumor cells in the initiation and progression of metastasis. We and others have observed that administration of culture conditioned media (CM) from metastatic human tumor cells results in viable bone marrow (BM)-derived "premetastatic niches" in target secondary organs. Notably, these niches actively recruited tail vein injected tumor cells to generate stable metastases. These observations led to the hypothesis that successful establishment of pulmonary metastases by malignant primary tumors must be preceded by the recruitment of BM-derived cells by the local microenvironment in the lung stroma. The natural extension of this hypothesis is that the activation of the local stroma is mediated by tumor-secreted protein(s) that are disseminated in the peripheral circulation. Conversely, we have also determined that CM from non-metastatic cells is unable to induce the formation of these premetastatic niches. We have identified prosaposin as a tumor-secreted protein that inhibits metastatic spread by stimulating the expression of p53 and its target gene, the antiangiogenic protein thrombospondin-1 (Tsp-1). Furthermore, we have determined that prosaposin is able to inhibit the migration of cells that comprise the premetastatic niche in an in vitro assay. Thus, one aim of this proposal is to determine the mechanism by which prosaposin inhibits premetastatic niche formation and to identify the minimal active region of prosaposin, which may serve as the basis for novel anti-metastatic therapeutic agents. Meanwhile, the other major aim of this proposal is to determine the therapeutic potential of targeting prosaposin as well as cellular components of the niche as an approach to impair productive metastasis initiation and progression in physiological mouse models of pulmonary metastasis. We propose an integrated and systematic approach that combines cell-based assays and in vivo mouse models of pulmonary metastasis to dissect the molecular mechanisms of tumor-initiated premetastatic niche formation in the lung stroma. Therapeutic targeting of metastasis initiation has tremendous promise for cancer patients who are likely to die of pulmonary metastasis. The lungs are one of the most frequent sites of metastasis by human primary tumors, and lung metastasis is one of the leading causes of death in cancer patients due to the invasive nature of the disease and resistance to current treatment modalities. In this grant, we will elucidate molecular mechanisms by which prosaposin inhibits premetastatic niche formation and to identify the minimal active region of prosaposin, which may serve as the basis for novel anti-metastatic therapeutic agents. We will evaluate the therapeutic potential of prosaposin as well as cellular components of the niche as an approach to impair productive metastasis initiation and progression in physiological mouse models of pulmonary metastasis. Therapeutic targeting of metastasis initiation has tremendous promise for cancer patients who are likely to die of pulmonary metastasis
Keywords: Angiogenesis Antagonists; Angiogenesis Blockers; Angiogenesis Inhibitors; Angiogenetic Antagonists; Angiogenic Antagonists; Angiostatic Agents; Animals; Anti-Angiogenetic Agents; Anti-Angiogenic Agents; Anti-Angiogenic Drugs; Antiangiogenesis Agents; antiangiogenic; Antiangiogenic Agents; Assay; base; Bioassay; Biologic Assays; Biological Assay; Blood Circulation; Bloodstream; Bone Marrow; Bone Marrow Blood-Deriving Cell; Bone Marrow Blood-Forming Cell; Bone Marrow Cells; Bone Marrow Transplant; Bone Marrow Transplantation; Breast Neoplasms; Breast Tumors; cancer cell; cancer metastasis; Cancer of Prostate; Cancer Patient; Cancers; Cause of Death; CD11b; Cell Locomotion; Cell Migration; Cell Migration Assay; cell motility; Cell Movement; Cells; Cellular Migration; cellular targeting; Circulation; Clinical; Conditioned Culture Media; Conditioned Medium; CR3A; Culture Media, Conditioned; diphtheria toxin receptor; Diphtheria Toxin Sensitivity; diptheria toxin receptor; Disease; Disease Resistance; disease/disorder; Disorder; DT-R; DTR; DTR Protein; DTS; Endothelial Cells; Fibroblasts; Flt-1; FLT1; FLT1 Receptor Tyrosine Kinase; FLT1 RTK; fms-Like Tyrosine Kinase; gene product; Gene Targeting; Genes, p53; Grafting, Bone Marrow; Grant; HB-EGF; HB-EGF precursor; HBEGF; HEGFL; heparin-binding epidermal growth factor-like growth factor precursor; Human; Human, General; Immunocompetent; In Vitro; in vitro Assay; in vivo; Inhibitors, Angiogenetic; Inhibitors, Angiogenic; ITGAM; ITGAM gene; Lung; Lung Parenchyma; Lung Tissue; lymph gland; Lymph node proper; lymph nodes; MAC-1; MAC1A; Maintenance; Maintenances; malignancy; Malignant; Malignant - descriptor; Malignant Cell; Malignant neoplasm of prostate; Malignant Neoplasms; Malignant prostatic tumor; Malignant Tumor; Malignant Tumor of the Prostate; Mammals, Mice; Mammary Cancer; Mammary Neoplasms; mammary tumor; Man (Taxonomy); Man, Modern; Maps; Marrow Transplantation; Mediating; Metastasis; Metastasis to the Lung; Metastasize; Metastatic Neoplasm; Metastatic Neoplasm to the Lung; Metastatic to; Metastatic Tumor; Metastatic Tumor to the Lung; Mice; Migration Assay; MO1A; Modality; Modeling; Molecular; Mortality; Mortality Vital Statistics; Motility; Motility, Cellular; mouse model; Murine; Mus; mutant; Nature; Neoplasm Metastasis; neoplasm/cancer; neoplastic cell; Neovascularization Inhibitors; neutralizing antibody; novel; Organ; P53; Peripheral; Physiologic; Physiological; prevent; preventing; Primary Neoplasm; Primary Tumor; Principal Investigator; Prostate CA; Prostate Cancer; Prostatic Cancer; Proteins; Proto-Oncogene Protein flt; public health relevance; pulmonary; pulmonary metastasis; Receptor Tyrosine Kinase, Class V; recruit; Recruitment Activity; Relative; Relative (related person); Resistance; resistance to disease; Resistance, Disease; resistant; resistant disease; resistant to disease; Respiratory System, Lung; Reticuloendothelial System, Bone Marrow; Reticuloendothelial System, Lymph Node; Role; Secondary Neoplasm; Secondary Tumor; short hairpin RNA; shRNA; Site; small hairpin RNA; social role; Stromal Cells; Structure of parenchyma of lung; Tail; Targetings, Gene; THBS1; Therapeutic; Therapeutic Agents; therapeutic target; Thrombospondin 1; Time; TP53; TP53 gene; Transgenic Mice; TRP53; TSP; TSP-1; TSP1; tumor; Tumor Cell; Tumor Cell Migration; Tumor Protein p53 Gene; tumor xenograft; Tumor-Secreted Protein; Tyrosine Protein Kinase FRT; Tyrosine Protein Kinase Receptor FLT; Vascular Endothelial Growth Factor Receptor-1; VEGF Receptor flt-1 Protein; VEGF Receptor, FLT; VEGFR-1; VEGFR1; Veins; Work; Xenograft Model
Relevance: Principal Investigators: Mittal, Vivek and Watnick, Randolph, S. The lungs are one of the most frequent sites of metastasis by human primary tumors, and lung metastasis is one of the leading causes of death in cancer patients due to the invasive nature of the disease and resistance to current treatment modalities. In this grant, we will elucidate molecular mechanisms by which prosaposin inhibits premetastatic niche formation and to identify the minimal active region of prosaposin, which may serve as the basis for novel anti-metastatic therapeutic agents. We will evaluate the therapeutic potential of prosaposin as well as cellular components of the niche as an approach to impair productive metastasis initiation and progression in physiological mouse models of pulmonary metastasis. Therapeutic targeting of metastasis initiation has tremendous promise for cancer patients who are likely to die of pulmonary metastasis
Project start date: 2010-02-01
Project end date: 2014-12-31
Budget start date: 1-JAN-2011
Budget end date: 31-DEC-2011
PFA/PA: PA-07-070
5R01CA135417-02 (2011): $473497
Grants awarded to S Randolph
NEW YORK COLUMBIA COLLABORATIVE SPOTRIAS
S Randolph, Elizabeth K. Harris Professor Of Neurolo
Columbia University Health Sciencescity: New York country: United States (us)
Grant 3P50NS049060-07S1 from National Institute Of Neurological Disorders And Stroke
Abstract: We have recently argued that stroke recovery is best defined as the process of improvement of the initial impairment rather than as the recovered endpoint itself (for example, change in Fugl-Meyer motor score (AFM) from baseline to 90 days post-stroke). This perspective facilitates the investigation of the biological mechanisms involved with recovery rather than simply looking at the result of the process once it has occurred. In the first SPOTRIAS grant three important discoveries were made that altered the landscape of the investigation of stroke recovery, and which provide the scientific groundwork for our current proposed line of investigation. The first discovery was the principle of proportional recovery, in which we showed that all stroke patients with mild-to-moderate deficits tend to recover a specific proportion (-70%) of their maximum potential recovery with a high degree of predictability (R=.90). Initially described with regard to motor function, the same principle also appears to hold for recovery of language function. Second, in patients with severe initial impairment there is much greater variability in recovery - some follow proportional recovery, and some recover negligibly. These non-recoverers, indistinguishable clinically from proportional recoverers in the first week post-stroke, represent an important class of patient to characterize further; The third discovery, which satisfied the primary specific aim of the original SPOTRIAS grant, was that there is a significant correlation between functional magnetic resonance imaging (fMRI)-measured brain activation acquired at an average 2 days after stroke onset and the degree of motor recovery of the neurological impairment over the subsequent 3 months. The overall goal of this grant is to derive a clinically relevant tool for predicting spontaneous recovery in individual patients within the first few days after stroke, and through this process investigate the mechanistic role of 3 variables that we hypothesize are important correlates of AFM initial impairment, DWI lesion load on the corticospinal tract (CST), and expression of the fMRI "recovery pattern." This goal will be achieved by first validating the principle of proportional recovery with explicit examination of the influence of rehabilitation, then determining the correlation between degree of disruption of the CST and the patient´s initial impairment and subsequent recovery, and finally by selecting the model that best predicts AFM using the 3 variables alone and in combination. The second goal, which will draw on additional imaging expertise from the MGH SPOTRIAS site, is an important guide to further research into interventions, and will be studied by testing hypotheses from the extant literature about the necessity and sufficiency of corticospinal tract (CST) pathways in recovery. Sixty acute stroke patients from the stroke services at Columbia and the MGH will be studied with this multi-modal approach. RELEVANCE Stroke is the third leading cause of mortality and the leading cause of disability in adults in the US. A better understanding of the mechanisms of stroke recovery will allow us to predict who is likely to recover well and to target specific interventions for development that will enhance the recovery process
Project start date: 2004-07-01
Project end date: 2014-07-31
Budget start date: 1-AUG-2011
Budget end date: 31-JUL-2012
3P50NS049060-07S1 (2011): $880510
5P50NS049060-07 (2011): $1279480