Bone found to abet Lung Cancer

Natasha Vinod

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.

Work discussed:

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

Featured Image Credits:

By Bruce Blaus. Blausen.com staff (2014). “Medical gallery of Blausen Medical 2014” WikiJournal of Medicine 1 (2).

 

47 Replies to “Bone found to abet Lung Cancer”

  1. This is a lovely read, very interesting correlation. I am now more curious than ever to understand the role of our marrows in inhibiting/treating malignant tumors.

    Like

  2. Interesting read. Very well explained too. A new frontier to deal with lung cancer could be on its way with this correlation in place.

    Like

  3. This is one of few articles on malignancy that actually one can comprehend
    .
    Same time scary
    Diseased cells communicating with & influencing healthy cells
    .
    But reassuring that knowing this disruption of communication could ease treatment
    .

    Like

  4. Namaste Beta !!!! It’s an amazing article written by you that UNPADH INSAAN like me could understand great deal out of it. The metrology adopted by you is awesome. Every word mentioned therein is meaning full explaining every aspect in detail. Thank you. Good luck and God speed.

    Like

  5. The remote connections made by the capricious cancer between two major organs is well explained in the article. Whether there are more such interplays could be the subject of further inquires.
    Hopefully, these cutting edge research activities should result in better cure for cancer.

    Like

  6. Interesting article. A great attempt at simplifying the complex maze of cancer immunity in a digestible format. Kudos to the author. Keep up the good work

    Like

  7. An excellent work… few of the Keralites are already in the clutches and many more in pipeline….A major cause of concern for us…

    Nitasha, your efforts wl enlighten many on this subject.
    Keep progressing the good work.
    God bless….

    Like

  8. Thank you all for the overwhelming response to the post! Thank you for reading 🙂 Thank you team OncoBites for the opportunity!

    Like

  9. Awesome article…superbly explained in simple language for even any laymen to understand the complexity of cancer cells progress…thanx Natasha

    Like

  10. “Cancer” remains as dreaded a word as it did half a century ago. The only difference is, that while in those times we heard of it as a disease afflicting some distant acquaintaince, today most of us have had a close relative or friend having been struck by this disease. The earlier perception that it was a disease of only the old, too, has undergone a change.
    This article, though necessarily a bit technical due the nature if its topic, was informative even to a layman like me. I am also sure that it also helps contribute to the awareness of the disease and sensitising people to it and to the wide variety of efforts by the global medical fraternity.

    Like

  11. Very good article. Being a former biology student it was easy for me to understand, but I must say it has been written so well that even a layman can understand exactly what is explained!
    Well researched, didn’t know that cancer cells affected bone marrow like that!
    Well done Natasha

    Like

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out /  Change )

Google+ photo

You are commenting using your Google+ account. Log Out /  Change )

Twitter picture

You are commenting using your Twitter account. Log Out /  Change )

Facebook photo

You are commenting using your Facebook account. Log Out /  Change )

Connecting to %s