Rudolph Virchow was one of the first physicians to study diseases from the standpoint of cells. He applied his cell theory “Omnis cellula e cellula” (“every cell originates from another cell”) to the study of cancer and reasoned that cancer results from the failure of the regulatory mechanism of the cells to control cell division. With a relentless capacity to divide, cancer cells rapidly populate tissues and organs by displacing normal cells. What’s even more alarming is the rate at which cancer cells are evolving by means of random mutations and natural selection, yielding recalcitrant daughter cells that are more resistant to treatment than previous generations of cancer cells. Recurrent mutations confer an unpredictability to cancer that results in unbridled growth and spread. As fresh evidence to the capricious nature of cancer, researchers from Harvard Medical School recently revealed the ability of lung cancer to remotely stimulate bone cells to acquire tumor-promoting properties.
Bone is a vital organ largely known for its protective and supportive function in the skeletal framework. The central cavity of bones, known as bone marrow, is also the principal site of blood cell production, a process called hematopoiesis. New blood cells are produced from hematopoietic stem cells (HSC) that make up the bone marrow. Blood cells differ by function; white blood cells, which make up the immune system, and red blood cells, which carry oxygen to tissues. The immune system offers several layers of defense against an infection. The primary layer, or innate immunity, consisting of a subtype of white blood cells called myeloid cells, are the first responders to infection. When the primary defense fails to eliminate the infection, the secondary layer, called adaptive immunity, is brought into play. White blood cells called lymphoid cells control the adaptive immune response. Cells from both the innate and adaptive immune system undergo hematopoiesis in the bone marrow, in a region known as the HSC niche. Aberrant hematopoiesis, typical of many cancer types, gives rise to transformed immune cells that lack antitumor activity. This drift to an abnormal phenotype is particularly common for cells of the myeloid lineage, and in many cancers, a high concentration of myeloid cells in the tumor microenvironment correlates with poor prognosis.
Having observed an increased bone mass in humans and mice with lung adenocarcinoma, the most common type of lung cancer, the authors suspected crosstalk between cancer and bone even in the absence of tumor invasion to bone tissue. Further investigation of the bone marrow of tumor-bearing mice revealed a spike in the population and activity of a special sect of bone forming cells called osteocalcin positive osteoblasts (Ocn+), osteocalcin being a protein expressed by mature osteoblasts. Furthermore, these cells overexpressed Fosl2 (a gene required for bone formation), explaining increased bone density in tumor-bearing individuals.
However, it was still unclear whether the elevated numbers and activity of osteoblasts in lung adenocarcinoma was associated with tumor progression. To examine this association, researchers experimentally reduced the number of osteoblasts in bone marrow in mice with lung adenocarcinoma. These mice exhibited slower tumor growth, insinuating a correlation between osteocalcin activity and cancer. Tumor-infiltrating immune cells impact tumor growth, often negatively. Accordingly, a special class of neutrophils (immune cells of the myeloid lineage and a major part of the innate immunity) were found to infiltrate the tumor tissue of mice with lung adenocarcinoma. Tumor-bearing mice with experimentally reduced Ocn+ numbers in the marrow were found to have a corresponding decline in the aforementioned subset of neutrophils in the tumor, identified as SiglecFhigh neutrophils. These neutrophils exhibit high expression of cell membrane proteins that bind to sugars called sialic acid found in animal tissues, hence the name SiglecFhigh (high expression of sialic acid-binding immunoglobulin-like lectin F) cells. Depletion of Ocn+ cells in the marrow not only led to the depletion of SiglecFhigh cells in the tumor, but also stalled tumor growth, indicating that not only is full-fledged tumor infiltration of SiglecFhigh neutrophils required for lung adenocarcinoma growth, but this is made possible by activated Ocn+ osteoblasts. It was further found that Ocn+ cells are activated by sRAGE (soluble receptor for advanced glycation end products), a circulating protein supplied to the bloodstream by tumor cells, which in turn supply SiglecFhigh neutrophils to the tumors. This discrete subset of neutrophils bears genes that support tumor growth associated processes.
Lung adenocarcinoma tumor development involves a vicious cycle of tumor signaling driven activation of osteoblasts, leading to recruitment of tumor homing neutrophils that foster tumor growth once inside the tumor microenvironment. In hindsight, tumors can have systemic effects even if locally contained, as in the case of adenocarcinoma. This understanding is very important for developing effective anticancer strategies that can intervene systemic alteration of host cells by cancer.
About the Author: Natasha is a doctoral student in the Joint Department of Biomedical Engineering at UNC Chapel Hill, and NC State University. Her research investigates the use of novel micellar architectures for improving the delivery of anti-cancer drugs. Natasha holds an MS in Biotechnology with a concentration in Regulatory Affairs from the Johns Hopkins University.
Engblom, C., Pfirschke, C., Zilionis, R., Da Silva Martins, J., Bos, S. A., Courties, G., . . . Pittet, M. J. (2017). Osteoblasts remotely supply lung tumors with cancer-promoting SiglecF(high) neutrophils. Science, 358(6367). doi: 10.1126/science.aal5081
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By Bruce Blaus. Blausen.com staff (2014). “Medical gallery of Blausen Medical 2014” WikiJournal of Medicine 1 (2).