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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA135417-04
Application #
8403625
Study Section
Tumor Microenvironment Study Section (TME)
Program Officer
Jhappan, Chamelli
Project Start
2010-02-01
Project End
2014-12-31
Budget Start
2013-01-01
Budget End
2013-12-31
Support Year
4
Fiscal Year
2013
Total Cost
$492,966
Indirect Cost
$102,993
Name
Weill Medical College of Cornell University
Department
Surgery
Type
Schools of Medicine
DUNS #
060217502
City
New York
State
NY
Country
United States
Zip Code
10065
Li, Wenliang; Ai, Nanping; Wang, Suming et al. (2014) GRK3 is essential for metastatic cells and promotes prostate tumor progression. Proc Natl Acad Sci U S A 111:1521-6
Catena, Raul; Bhattacharya, Nandita; El Rayes, Tina et al. (2013) Bone marrow-derived Gr1+ cells can generate a metastasis-resistant microenvironment via induced secretion of thrombospondin-1. Cancer Discov 3:578-89