Abstract 3058: Bone marrow hematopoietic stem cell niche activation and mobilization fosters the metastatic niche

Abstract

Abstract Metastasis remains the main cause of mortality for patients with cancer. The process whereby a localized tumor becomes metastatic remains poorly understood. Metastasis was previously thought to be a late-stage, unidirectional migration of cells from the primary tumor to a distant site, due to acquired genetic mutations that conferred necessary metastatic attributes to the cell. However, current research demonstrates that dissemination is not a late phenomenon and although loss of metastasis suppressor genes or gain of acquired mutations can contribute to the metastatic phenotype, the cross-talk between the tumor and its microenvironment has proven to be a major driver of this process. We have found that recruited bone marrow-derived cells and changes in resident stromal cells form a microenvironment that is conducive to metastatic progression, termed the pre-metastatic niche. The recruited and resident cells that form this microenvironment are active areas of investigation. Because the bone marrow is the source for most of the recruited cell types in these distant tissue sites, we postulated that activation of the bone marrow's hematopoietic compartment plays a key role in metastatic progression. We sought to profile the changes that occur within the hematopoietic stem cell niche of the bone marrow and subsequent changes in hematopoiesis in the setting of tumor development. Within the bone marrow of tumor bearing mice we found increased proliferation of hematopoietic stem and progenitor cells. These cells are also increased in the circulation of both tumor bearing mice and patients with malignancy. Furthermore, we have determined that elevated levels of circulating hematopoietic progenitor cells can be predictive of metastatic risk, as those patients with the highest levels at diagnosis developed metastases. This biomarker may be useful in stratifying therapy for patients with localized disease who have the highest metastatic risk. Better understanding of the steps and individual factors required to establish a metastatic microenvironment can lead to novel adjuvant therapies to target this process. Citation Format: Amber J. Giles, Meera Murgai, Yorleny Vicioso, Steven Highfil, Crystal Mackall, Leonard Wexler, David Lyden, Rosandra Natasha Kaplan. Bone marrow hematopoietic stem cell niche activation and mobilization fosters the metastatic niche. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3058. doi:10.1158/1538-7445.AM2014-3058