Why Does Prostate Cancer Spread?

Medical treatment of metastatic prostate cancer is challenging and not appropriate for all patients. Luckily, prostate cancer is usually very slow to progress. 

Many patients will remain stagnant in a stage of localized prostate cancer. Others will continue rapidly, spreading locally and to other organs. 

Why is cancer progression so different among patients? Why does prostate cancer spread?

In this article, we’re covering the topic of prostate cancer metastasis. After considering the incidence and why it happens, we talk about prevention and how you know prostate cancer is spreading locally or to distant organs.

What is metastatic prostate cancer?

Metastatic prostate cancer is the clinical description of an advanced stage of the disease. In this phase, cancer is not limited to the initial tumor. Instead, this primary tumor grows, spreading to nearby organs, and then to distant areas. 

Initially, prostate cancer will remain in a localized tumor. It could stay like this for many years in most patients. But then, it continues growing, and new cancer cells adopt new gene mutations. 

Such changes include lower adhesion between nearby cells. Cancer is no longer anchored to the prostate gland and ultimately migrates through the blood or lymph.

That is how metastatic prostate cancer initiates, and we can detect it through imaging techniques. For many years, CT scans were used to detect this type of spread. Now it is diagnosed through more advanced techniques: MRI and PET.

An essential aspect we should highlight about metastatic prostate cancer is resistant to treatment. This type of advanced prostate cancer may not respond to usual cancer treatments. It requires systemic therapy and it can develop resistance to hormone therapy (1).

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What is the likelihood of prostate cancer spreading?

Cancer behaves like a species competing for survival, similar to Darwinian evolution. More and more subclones of cancer emerge in the primary tumor. The more aggressive cells survive for a longer time and continue creating subclones. 

Among these, the most aggressive continue surviving. This is how the disease progresses into a more dangerous stage in every step.

Thus, the question is not if cancer will spread but when. All cancers may ultimately spread, but since prostate cancer tends to progress very slowly, older men usually don’t live through this process. 

They may die for unrelated causes, especially if prostate cancer is diagnosed after age 70 years. Considering patients who die for unrelated reasons, extra-prostatic disease risk is very high (30-60%).

Younger prostate cancer patients are more likely to live through the initial and intermediate stages. The younger you are at the moment of diagnosis, the more likely it is to experience metastasis. You’re giving cancer more time to reach that stage. It also depends on the genes involved in the process and your risk factors (2).

According to recent statistics, the incidence of metastatic prostate cancer is rising. The spread of this type of cancer is becoming more common with passing years to an alarming degree. 

Metastatic prostate cancer was 72% more common in 2013 in comparison to statistics by 2004. Meanwhile, low-risk prostate cancer decreased by 37%. In other words, cancer spread is becoming more likely. The exact cause of this change through the years is still unknown (3).

Why does prostate cancer spread?

We don’t know exactly why metastatic cancer is becoming more common in modern days. However, we have a hint of how it spreads in the body and why.

As noted above, cancer goes through an evolutionary process. The most aggressive cells survive better in this environment, and they keep advancing toward metastasis. All of these changes are triggered by genetic alterations to the prostatic tissue DNA.

Overlapping genetic alterations, over and over again, change healthy prostate cells into something entirely different. In the end, cells are dramatically different in their characteristics and metabolism. They become immortal, resistant to the immune system, and lose their anchor to the prostate tissue. Not having an anchor leads to metastasis.

Such anchor depends on several proteins and structures. They include:

Gap junction

It is the most common type of junction between cells. They not only keep cells together but also favors their communications. They are closely bound and in metabolic or electric contact to act as a tissue instead of individually. 

Adhering junction

A very complex anchor between cells. It contains actin filaments, glycoproteins, and complex structures called desmosomes. All of these structures contribute on their own to keep cells bound to their tissue.

Cancer spreads because these junctions are destroyed. DNA damage makes it impossible to code for these molecules and structures. They are not produced anymore, and cells become loose. 

Meanwhile, there’s an overgrowth of blood vessels as a part of cancer development. The blood flow increases, and every day those loose cells are more likely to dislodge and travel through the blood.

Once they reach the blood or lymphatic vessels, cancer cells behave like potential seeds. They reach a new tissue, use it as soil, and continue dividing. A new tumor is found, and it is called a secondary tumor or metastasis. Once metastasis is found, it means that cells are very loose. This process has probably been repeated for a long time in different body parts (4).

The latter holds true in almost every type of cancer. But there’s something special we should highlight about prostate cancer. This type is androgen-driven, which means that testosterone is involved in tumor growth and metastasis.

That is why hormone therapy is fundamental in case of metastasis. Androgen deprivation therapy has been the mainstay therapy of metastatic prostate cancer for over 70 years. 

Not having androgens around slows prostate cancer progression. It may even induce apoptosis in prostate cancer cells and reduce tumor mass dramatically.

But after a while, metastatic cancer may also become resistant to this type of treatment. When that happens, it is called castration resistant prostate cancer. This type of cancer is usually more aggressive than the average and has a poor prognosis (5).

Can you prevent prostate cancer from spreading?

The only 100% reliable way to prevent cancer from spreading is by taking it down while it is still localized. Other than that, we can only slow its progression or keep a careful look at it for any alarming sign. 

Some patients treat their prostate cancer with a combination of surgery, radiation therapy, and other treatments. 

Other patients may engage in watchful waiting or active surveillance. It consists of following-up cancer when it has a very low chance of spreading.

A potential method to prevent prostate cancer from spreading in the future

Recent studies have detected a transcription factor known as STAT3 as a promoter of prostate cancer metastasis. It has been proposed as a potential target to inhibit (prevent) metastasis. 

A study published in 2021 showed for the first time how a STAT3 inhibitor could obstruct the progression of prostate cancer. In other words, it won’t allow prostate cancer to spread to the bone (6).

However, we should note that the latter is the first study performed in animal models. It should be replicated and tested several times in clinical trials before finding an application in humans.

Where does prostate cancer spread?

One of the most recent studies involving a nationwide sample of near 75,000 patients considered the answer to this question.

The most common sites of metastasis in advanced prostate cancer included (7):

  • Local spread: We should first consider local spread, which comes before metastasis. We also call it locally advanced prostate cancer. Local spread is found in the pelvic organs, rectum, and seminal vesicles. Patients with metastasis almost always had local spread before leaving the pelvis.

  • Bone metastasis: This accounts for 85% of metastasis sites. The bone matrix is a very common target organ. It attracts cancer cells as a blood and nutrient-rich area where they can easily thrive.

  • Metastasis in distant lymph nodes: They are lymph nodes located anywhere but the pelvic region. It accounts for 10% of metastasis sites. It is a sign of lymphatic spread instead of blood-borne spread.

  • Liver metastasis: Another 10% of these patients had metastasis in the liver.

  • Metastasis in thoracic organs: This is mainly lung metastasis. It accounts for 9% of metastasis sites in prostate cancer patients.

According to this study, one out of five patients with advanced disease had more than one metastatic site.

Signs that prostate cancer has spread

We mentioned in this article active surveillance as one way to deal with prostate cancer. This type of management relies on signs, symptoms, and diagnostic tests to control cancer. 

These patients would likely run PSA tests and digital rectal exams every six months. Doctors may recommend they get recurrent prostate biopsies every 1-3 years.

But signs and symptoms are also important. Thus, it is worthwhile to consider the following alarm signs:

  • Bone pain: It is the most critical sign of bone metastases. It can be located in any part of the body, more commonly long bones of the extremities and the back. Prostate cancer bone metastases lead to a high risk of spinal cord compression and other complications.

  • Jaundice: In this case, it is a sign of liver involvement. There are many causes of jaundice, and one of them is liver metastasis.

  • Chronic fatigue: It is a sign of advanced prostate cancer, whether locally spread or metastatic.

  • Significant weight loss: More pronounced weight loss is a sign of more advanced disease.

Keep in mind that we should treat the prostate cancer before these symptoms show up. Once they do, the prognosis can be poor.

Conclusion

Metastatic prostate cancer risk is increasing through the years. These advanced prostate tumors develop due to overlapping DNA damage. Cells become loose in the prostate gland and finally migrate through the blood or lymphatic circulation.

The most common site of metastasis is the bone tissue. Thus, a bone scan is the first thing a doctor would run if they suspect a distant spread. The best thing we can do is treat the disease promptly. However, the treatment depends on age and the likelihood of progression.

Preventative treatment for prostate cancer progression is under active research. It is currently in a very early stage of development. In the future, it may block metastasis to the bone, possibly keeping the disease into stage IV prostate cancer.  

Next Up

metastatic-cancer

Read our Treatment Guide of Metastatic Prostate Cancer.

Sources

  1. Sartor, O., & de Bono, J. S. (2018). Metastatic prostate cancer. New England Journal of Medicine, 378(7), 645-657. https://pubmed.ncbi.nlm.nih.gov/29412780/
  2. Gundem, G., Van Loo, P., Kremeyer, B., Alexandrov, L. B., Tubio, J. M., Papaemmanuil, E., … & Bova, G. S. (2015). The evolutionary history of lethal metastatic prostate cancer. Nature, 520(7547), 353-357. https://pubmed.ncbi.nlm.nih.gov/25830880/
  3. Weiner, A. B., Matulewicz, R. S., Eggener, S. E., & Schaeffer, E. M. (2016). Increasing incidence of metastatic prostate cancer in the United States (2004–2013). Prostate cancer and prostatic diseases, 19(4), 395-397. https://pubmed.ncbi.nlm.nih.gov/27431496/
  4. Knights, A. J., Funnell, A. P., Crossley, M., & Pearson, R. C. (2012). Holding tight: cell junctions and cancer spread. Trends in cancer research, 8, 61. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3582402/
  5. Alva, A., & Hussain, M. (2013). The changing natural history of metastatic prostate cancer. The Cancer Journal, 19(1), 19-24. https://pubmed.ncbi.nlm.nih.gov/23337753/
  6. Thulin, M. H., Määttä, J., Linder, A., Sterbova, S., Ohlsson, C., Damber, J. E., … & Persson, E. (2021). Inhibition of STAT3 prevents bone metastatic progression of prostate cancer in vivo. The Prostate, 81(8), 452-462.
  7. Gandaglia, G., Abdollah, F., Schiffmann, J., Trudeau, V., Shariat, S. F., Kim, S. P., … & Sun, M. (2014). Distribution of metastatic sites in patients with prostate cancer: a population‐based analysis. The Prostate, 74(2), 210-216. https://pubmed.ncbi.nlm.nih.gov/24132735/
  8. Prins, R. C., Rademacher, B. L., Mongoue-Tchokote, S., Alumkal, J. J., Graff, J. N., Eilers, K. M., & Beer, T. M. (2012, January). C-reactive protein as an adverse prognostic marker for men with castration-resistant prostate cancer (CRPC): confirmatory results. In Urologic Oncology: Seminars and Original Investigations (Vol. 30, No. 1, pp. 33-37). Elsevier. https://pubmed.ncbi.nlm.nih.gov/20207556/
  9. Lara, P. N., Ely, B., Quinn, D. I., Mack, P. C., Tangen, C., Gertz, E., … & Van Loan, M. D. (2014). Serum biomarkers of bone metabolism in castration-resistant prostate cancer patients with skeletal metastases: results from SWOG 0421. JNCI: Journal of the National Cancer Institute, 106(4). https://pubmed.ncbi.nlm.nih.gov/24565955/
Alternative Text

Dr Alberto Parra

Dr. Alberto Parra is a Medical Doctor and clinical researcher with extensive experience in diagnostic imaging and sports medicine. He's also interested in nutrition, fitness and family medicine, with expertise and continuing education on preventive healthcare and evidence-based medicine. He provides consultancy services to a number of individuals and entities who require medical validation of their protocols, products, supplements, and medical contents.

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