Sympathetic Nervous System Control of Disseminated Tumor Cell (DTCs) Dormancy
Abstract
Prostate cancers (PCa) have an astonishing ability to disseminate to, invade, and survive in the bone marrow. Once there, tumor cells may lie undetected or dormant for years. How these cells become dormant and how they become reactivated to cause lethal disease remains unknown. Recent findings suggest that the metastatic process is functionally similar to the migrational or "homing" behavior of hematopoietic stem cells (HSC) to the bone marrow. Our previous work has drawn heavily on establishing parallels between HSC homing and the homing of PCa cells to the marrow. As a result, we were the first to demonstrate that PCa cells use a pathway that HSCs use to gain access to the marrow. Taking the analogy one step further, most HSCs are quiescent in the marrow yet they can be released from quiescence and their home in the marrow by signals from the central nervous system. Our work in this proposal will determine if PCa cells use the same signals as HSCs do to become dormant/quiescent in the marrow. The reason that this is so important is that once we know how metastatic cells become dormant, we can design strategies to maintain the disease as a chronic but controlled non-lethal condition. This knowledge is also critical as it may position us to eradicate these metastatic cells with existing chemotherapies that currently only target proliferating cells. Our investigations will focus on the fundamental mechanisms relating to metastasis in PCa. As alluded to above, HSC movement into and out of the bone marrow is regulated by nerve signaling in the marrow emanating from central nervous system. Likewise, it is well known from clinical observations that metastatic lesions are often found identified in individuals years after initial treatment, but shortly following physiologic stress. These observations suggest a link between the sympathetic nervous system and tumor relapse. Taking our HSC analogy a step further, we hypothesize that neural signals activated during times of physiologic stress release PCa from the signals that regulate their dormancy in marrow. To test our hypothesis, we will explore how the sympathetic nervous system (SNS), (e.g., the flight or fight system) shown to regulate HSC activities in marrow, regulates the ability to regulate PCa growth in bone marrow. In this proposal, we will determine (1) how signals from the SNS regulate the proliferation of PCa cells in marrow, (2) if interrupting SNS signaling will facilitate getting PCa cells out of the marrow where they may be more effectively killed with chemotherapy, and (3) in human samples if nerves are really associated with metastastic progression. We are confident that such observations are relevant to a more complete molecular understanding of the behavior of prostate cancer cells and that the new insights derived will lead to the development of innovative strategies to minimize primary tumors and their and malignant spread. Should our investigations prove fruitful, it may be possible to rapidly translate this information into human clinical trials. In this context, there exist many therapies that alter SNS signaling including selective and non-selective SNS blockers (e.g., beta-blockers), and several biotechnology companies are developing synthetic drugs to regulate HSC function in an effort to treat malignant disease. These studies may provide additional rationale for using drugs already underdevelopment and may also identify other targets that may be useful to treat other cancers. Thus, it may be possible to establish partnerships with such enterprises to determine whether similar strategies can be used minimize the consequences of prostate cancers.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510637
Entities
People
- Russell S. Taichman
Organizations
- United States Army
- University of Michigan