Study Reveals a New Pathway for Fighting Tumor Growth in Prostate Cancer Metastasized in Bone

Prostate cancer, in its most advanced stage, spreads tumor-producing cells through the bloodstream or lymphatic system to other areas of the body. For 65 to 80% of men with this aggressive form of the disease, the metastasis spreads to the bone with poor survival rates once this occurs [1]. A recent study conducted by researchers at the University of Michigan (U-M) and published in the Journal of Clinical Investigation has opened the door to a new understanding about rapid tumor growth in bone tissue[2]. This study has revealed a promising new pathway for the development of effective late-stage prostate cancer treatments and therapies.

Major Treatment Goal: Prevention of Bone Metastasis

Once prostate cancer spreads to bone, tumor growth is rapid. Patients in this stage experience serious symptoms that include pain, bone fractures, nerve compression and hypercalcemia[3]. Treatment at this point is palliative, with the goal of improving survival and mobility, relieving pain, and preventing complications. The U-M researchers note that prostate cancer cells that spread to bone encounter “a protective and supportive microenvironment that promotes metastatic outgrowth.”[2] Experiments in their study were designed to explore the factors contributing to this rapid tumor growth in bone with the eventual goal of developing therapeutics for men with bone metastasis from prostate cancer.

The Tumor Growth Paradox

In the body, the immune response triggers cells called phagocytes to continually engulf and absorb dead and dying cells. The process is known as efferocytosis, and it is a normal occurrence in both healthy people and individuals with cancer. However, when certain cancers (like prostate cancer) are present in bone, the process paradoxically speeds tumor growth. This action is not well understood, and according to study lead author, Hernan Roca, “In the presence of cancer, uncontrolled cell growth is also accompanied by a high, or significant, amount of cancer cell death.”[4]

“The challenge for the future,” continues Roca, “is to understand how to treat these patients to avoid this pro-inflammatory and tumor-promoting response, while still preserving the essential function of cell removal.”[4] Cancer therapy leads to cell death, which requires removal of the dead cells, but unfortunately also seems to result in cancer progression.

Understanding Efferocytosis as a Factor in Growth of Prostate Cancer Tumors

To better understand how the immune response and efferocytosis contribute to advancing cancer metastasis in bone, the U-M researchers developed a model for prostate cancer bone tumors in mice. They noted that molecular factors in bone create an inflammatory environment that interacts with tumor cells to promote growth and increase cell stress and damage to tissue.

To study this response, they induced cancer cell death in mice with cancerous cells and non-cancerous cells.  They found that removal of dead cancerous cells cause a different reaction than removal of dead non-cancerous cells. Results of the mouse experiments suggest that the body’s immune response responds selectively when absorbing dead cells based on the origin of the cells being cleared. Phagocytes absorbing cancerous dead cells appear to increase the expression of an inflammatory protein called CXCL5, which in turn leads to accelerated tumor progression, which does not appear to occur when clearing non-cancerous cells.[2]

Isolating CXCL5 as a Key Factor in the Rapid Spread of Prostate Cancer in Bone

Researchers next studied the specific role of efferocytosis of dead cancer cells in increasing CXCL5 levels, and the effect of this inflammatory protein in promoting metastatic cancer cell growth in bone. The production of CXCL5 was shown to increase with the death of cancer cells and efferocytosis. When mice were modified so they did not produce CXCL5, the tumor grew much less than in mice who normally produce the protein.[2] Since researchers hypothesized that increasing cell death and absorption of quickly spreading cancer would produce increased levels of the protein, they then tested patients with metastasized prostate cancer for serum levels of CXCL5. Results showed much higher levels of CXCL5 in these patients when compared to other patients whose prostate cancer had not metastasized.[4]

Potential for Effective New Prostate Cancer Treatments

The discovery of the vital role played by efferocytosis of dead tumor cells, and increased CXCL5 levels leading to metastatic prostate cancer progression, have opened a new pathway researchers hope will yield treatments and therapies to stop bone metastasis. Since cell death and efferocytosis are produced by cancer therapy, identifying CXCL5 as an important mediator of tumor progression is an important step in developing better treatments.

[2]

The 4Kscore Test Can Help in the Early Detection of Prostate Cancer

When a man receives an abnormal PSA reading during routine screening for prostate cancer, it can lead to avoidable prostate biopsies due to the low specificity of PSA for aggressive prostate cancer. The uncertainty that accompanies an abnormal PSA can result in stress and worry in many men who are at low risk of developing metastatic prostate cancer, but can also lead to men at higher risk not getting a biopsy when they should.

Men concerned about their risk of developing aggressive prostate cancer after an abnormal PSA can now turn to the 4Kscore Test, which measures four prostate specific kallikrein in the blood and combines these values with clinical findings, to provide the individual patient’s risk of aggressive prostate cancer.  Over fourteen studies in more than 22,000 men, including two prospective validation studies in the US, demonstrate the accuracy and clinical value of the 4Kscore in helping to make a prostate biopsy decision.

Prostate cancer has a much higher likelihood of successfully being treated before it metastasizes to bone, and early detection of aggressive cancer offers the best chance for effective treatment. If you are a man with an abnormal PSA talk to your physician about the advantages of the 4Kscore blood test to determine the right course of treatment.

 

  1. Weilbaecher KN, Guise TA, McCauley LK. Cancer to bone: a fatal attraction. Nat Rev Cancer. 2011;11(6):411–425.
  2. Roodman GD. Mechanisms of bone metastasis. N Engl J Med.

2004;350(16):1655–1664.

  1. Roca, H etal. Apoptosis-induced CXCL5 accelerates inflammation and growth of prostate tumor metastases in bone. J Clin Invest. 2018;128(1):248-266. doi:10.1172/JCI92466.
  2. Sandoiu A. Prostate cancer: How immune cells promote tumor growth. Med News Today. 28 Nov 2017.
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