San Francisco, CA USA (UroToday.com) Dr. Kenneth Pienta of Johns Hopkins University reviewed the biology of bone metastases and suggested ways in which understanding these processes may lead to therapeutic advances. He noted that one of the most important things to determine is what triggers prostate cancer cells to leave the prostate in the first place. To understand this, we can consider tumors as existing within complex ecosystems that continually interact with host cells, environmental factors like oxygen, nutrients, minerals, hormones, cytokines, and each other. A review of the principles of ecology reminds us that species
that have the resources they need within a given environment will not leave their niche; selective pressure to change is minimal for species that are perfectly adapted and supported within an environment. Given this, Dr. Pienta describes the “cancer swamp”, an ecosystem with limited resources due to a limited blood supply that selects for or favors a “super immigrant” cancer cell phenotype that migrates from the initial tumor site. These super immigrant cells become more common over the course of an individual’s disease, progressing from an initial population comprised predominantly of epithelial cells with weak grip to a population that is primarily populated with mesenchymal cells with a stronger grip. Without this selective pressure, cancer cells would not evolve the ability to metastasize in large numbers.
After leaving the prostate, cancer cells must have the ability to survive in circulation. Clumps of cancer cells mixed with white blood cells have been observed in mice. It is possible that clumps of cells may be better able to move through the circulation and survive the turbulence of the heart, though this is still an open question. Additionally it is unknown whether clumps of cells break passively off of the primary tumor, or if this is an active exit process.
Once out of the prostate, prostate cancer cells target the bone marrow and inhabit the niche of hematopoietic stem cells preferentially. Metastatic prostate cancer cells then attach to osteoblasts and become dormant for variable periods of time before being induced to proliferate. GAS6 receptors appear to be involved in the dormancy process, with high expression of AXL being associated with dormancy and high expression of Tyro3 being associated with heightened activity. The amount of expression of these receptors varies, with cells growing locally in the prostate or in metastatic sites expressing high levels of AXL, and cells metastasizing to new locations but not growing expressing high Tyro3.
A final question addressed by Dr. Pienta was whether there is are phenotypic or genotypic differences between cancers that progress to an oligometastatic state versus those that appear as systemic metastatic disease. More specifically, he questions whether the oligometastatic state is truly a distinct disease process that can be targeted and potentially cured, or whether it is simply an early point in the process of developing systemic metastatic disease. He notes that recent advances in imaging enabling with greater sensitivity for detecting metastatic sites, such as NaF PET/CT, seem to indicate that oligometastatic disease is not the distinct state we envisioned.
Dr. Pienta wrapped up his talk with a brief summary of his comments, and reminded the audience that there is much to learn about the biology of metastatic disease. The development of metastatic clones likely requires selective pressure from depleted resources that favors the survival of cells with a mesenchymal phenotype that can leave the primary tumor. Prostate cancer cells hone to hematopoietic stem cell niches and bind to osteoblasts when there. Although the founder cells of metastatic colonies appear to remain dormant for a period of time, a proliferative phenotype can develop. As scientists achieve greater understanding of this process, we will see the development of innovative strategies to counteract it.
Presented By:
Dr. Kenneth J. Pienta, MD
Johns Hopkins University School of Medicine
Reported By:
Alicia K. Morgans, MD, at the 2016 Genitourinary Cancers Symposium - January 7 - 9, 2016 – San Francisco, CA
Assistant Professor of Medicine Medical Oncologist
Vanderbilt - Ingram Cancer Center