Carcinoma Of The Prostate Biology Essay



Cancer is a group of over one hundred diseases characterised by abnormal uncontrolled cell growth. In a healthy body; cells grow, die and are replaced in a very controlled way. Damage or change in the genetic material (DNA) of cells by environmental or internal factors sometimes results in alteration of the DNA (gene expression) through various ways: DNA mutations (change in nucleotide sequence), gene amplification (production of copies of gene at one location on a chromosome), duplication/deletion of a gene etc. This can lead to cells that do not die and continue to multiply until a mass of cancer cells or tumour developed. Most cancer related deaths are due to metastasis, malignant cells that penetrate into the circulatory system and establish colonies in other parts of the body. [1]

In carcinoma of the prostate, the growth and multiplication of cells escapes from normal control. In addition there is apparent of aptosis, the important process of programmed cell death which normally regulates cell numbers. Carcinoma of the prostate usually begins in the peripheral zone, unlike benign prostatic hyperplasia which most often starts in the transitional zone around the prostatic urethra. Unlike the situation in benign prostatic hyperplasia where cell multiplication is much more controlled, in prostate carcinoma the malignant cells multiply out of control, begin to invade the stroma, the connective tissue of the prostate, and extend beyond it to the surrounding structures such as the seminal vesicles. Having breached the prostate capsule, the tumour is now able to spread more widely. Malignant cells may invade the lymphatic system, travelling to regional lymph nodes and then into the liver and/or lungs. If the tumour cells enter the blood stream they may also be carried to the bones as well as the liver and lungs. [2]

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The severity of prostate cancer is determined by what stage the cancer is in; T1 and T2 are when PC is limited only to the prostate gland, T3 when the cancer had spread through the prostate capsule and T4 when the cancer spread to other structures other than seminal vesicles (e.g., bladder neck, rectum, pelvic wall etc.). [3]


Prostate cancer is the most common diagnosed cancer in men. Around 338,000 men were diagnosed with prostate cancer in Europe in 2008, and about 913,000 Worldwide. It accounts for 24% (37,051) of all new cancer cases diagnosed in men in the UK. Lung cancer is the second most common followed by bowel cancer (colorectal). The rate of prostate cancer has tripled in the UK over the last 30 years (peeking in the early 1990's). Although, this can be due to the widespread use of the detection method called PSA test. The PSA testing can also be attributed to the increase of survival rate of prostate cancer (as it is responsible for early detection), where 3 out of 4 men can now survive beyond five years (compared to 1 in 3 in the 1970s). Prostate cancer incidence increase with age, more than half of prostate cancer cases in 2008 were diagnosed in men over 70 years old.

In 20008, there were more than 156,000 cancer deaths in the UK, and 27% of all deaths in the UK were due to cancer. Prostate cancer were ranked second among the 10 leading cancer-related causes of death for men in the UK in 2008, accounting for 12% (10,170) of all male cancer deaths.(Prostate accounted for more than 70,000 deaths in men in Europe and about 258,000 men worldwide.) Lung cancer remained by far the most common cause of death from cancer in men, accounting for 24% of all male cancer deaths in the UK. (Although, prostate cancer has a high survival rate if diagnosed early.) [4]

Figure 1: Number of new cases and age specific incidence rates, prostate cancer, UK 2008. [4]

Figure 3: diagram showing the position of the prostate and rectum. [5]Prostate Cancer and the prostate gland

The prostate is a gland found only in men, about the size of a walnut, and it is a part of the male reproductive system. It is located behind the base of the penis, in front of the rectum and below the urinary bladder surrounding the urethra (the tube that carries semen or urine from the bladder to the penis). See Figure 3. The prostate gland produces the fluid part of semen (which contains sugars and minerals that serve as nutrients to sperm). This fluid is white in appearance ("milky"), thin and alkaline that is secreted into the urethra at the time of ejaculation. It is probable that this alkaline fluid (accomplished through secretion from the seminal vesicles) help to increase the lifespan and motility of the sperms by neutralizing the acidity of the vaginal tract. The prostate gland helps control urination (by pressing against the part of the urethra). It can also prevent infections in the urinary and reproductive tract. [3, 5]

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The prostate is not just one gland but rather a collection of many small glands which are connected by hundreds of tiny ducts or "pipes" which carry the liquid part of the semen that these glands produce. The prostate has 4 different areas described as zones (See figure below):

Peripheral zone: This is located at the backside of the prostate gland surrounding the distal urethra. This zone is most susceptible to cancers, about 70-80% of prostate cancers originate here.

Central zone: The central zone surrounds the ejaculatory ducts, and accounts for only 5-8% of prostate cancers. Although a low number of cancer originate here, these cancers are more aggressive and tend to invade the seminal vesicles.

Transition zone: This zone surrounds the prostatic urethra that passes through the prostate. The transition zone is the common site responsible for benign prostate enlargement. About 10-20% of prostate cancers originate here.

Anterior fibro-muscular zone: This region consists of only fibrous and muscle tissues. [6]

Figure 4: showing the various zones of the prostate gland. []The prostate needs male sex hormones, androgens, to grow, function and work properly. The male hormones are responsible for the male sex characteristics. The main male hormone is testosterone, produced mainly (95%) in the testicles and small amounts (5%) are produced in the adrenal glands. Testosterone can gets converted to the more portent hormone; dihydrotestosterone which regulates the prostate. (See Role of hormones in prostate cancer and the steroidal cascade below for more detailed information). [6]

Some of the symptoms of PC include problems with urination: frequent urination (especially at night), difficulty passing urine, blood in the urine/semen, pain in the back and upper thighs.

Diagnosis of prostate cancer can be confirmed with two tests; digital rectal examination and blood test to measure prostate-specific antigen (PSA) levels. The procedure of digital rectal examination involves the doctor feeling the prostate (with gloves) through the rectum to find nodules. The PSA test measure the levels of PSA in the blood, which is a protein produced in excess by prostate cancer cells. [3]

Risk factors

The strongest known risk for prostate cancer is age. Recent studies of age-specific incidence reveal that the risk of prostate cancer continues to increase as the man grows older. Figure XX shows that the risk is low in men under 50, and it starts to increase sharply after the age of 55 and peaks at 70-74 (and declines slightly afterwards). Around 76% of all prostate cancer cases are diagnosed in men over the age of 65. This was confirmed by autopsy studies as well as incidence surveys, where about 80% of the men over the age of 80 had prostate cancer. Peter H. et al showed that prostate cancer can be tied with a long induction period that may start with incipient lesions at the age of 20-30.

International variations in the incidence rates of prostate cancer around the world indicate that the risk of prostate cancer is affected by ethnicity/race. In the UK, black African and black Caribbean men have twice, and sometimes triple, the risk of being diagnosed or dying from prostate cancer compared to white men. On the other hand, the risk is significantly lower than the national average in Asian men. [7]

Figure 2 below shows the results from a study performed in 2002, where they compared the incidence rates and mortality of prostate cancer in white and black men in the USA. The results suggest that indeed black American men have higher incidence rates (60% more) than white American men, and that they are more than twice as likely to die from prostate cancer. The study also confirmed that Asian Americans have lower risk. However, lifestyle factors are important and play a role in the incidence rates. Migration studies showed that, when men move from a low-risk country (e.g. South Asia) to a higher-risk country (e.g. the UK) they have higher risk of prostate cancer than those living in their original country. Various studies have been done to try to explain the reasons for these differences. Some of them suggest that socioeconomic status, environmental factors and genetic factors differences are involved. Other factors include family history, diet, having multiple sexual partners. [7, 8, 9]

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Figure 2: Age-adjusted incidence and mortality of prostate cancer in United States, 1973-1999. [9]

The Steroidal Cascade

Cholesterol is the main precursor of the three major steroid hormone families: mineralocorticoids, glucocorticoids and sex steroids. The biosysthetic pathway of these hormones, known as the steroidal cascade, involves complex chain reactions where a specific enzyme catalyses every step. The majority of these enzymes belong to the cytochrome P450 family of enzymes.

The production of these steroids starts in the mitochondria, when cholesterol gets converted to pregnenolone (Figure3) by an enzyme called P450CSCC (cholesterol side chain cleavage enzyme). Afterwards, pregnenolone enters the endoplasmic reticulum (by passive diffusion), where it acts as pregnane, leading to different metabolic pathways.

Mineralocorticoids are produced in the outer zone of adrenal cortex (zona glomerulosa), when pregnenolone gets converted to progesterone by 3B-HSD enzyme (3B-hydroxysteroid dehydrogenase) which after various steps gets converted to the final product; aldosterone (the main mineralocorticoid). Aldosterone promotes sodium transport in the kidney and gut, thus acting as a regulator of electrolyte homeostasis and blood pressure control.

On the other hand, glucocorticoids are produced in the inner zones of the adrenal cortex (mainly in the zona fasciculata, with a small amount being produced in the neighbouring cells of zona reticularis). When pregnenolone enters the endoplasmic reticulum, via passive diffusion, it can be converted to two different products (Figure XX), either progesterone (via 3B-HS) or 17a-hydroxypregnelone (via the enzyme 17α-hydroxylase/17,20-lyase).

If the product is progesterone, it gets converted to 17α-hydroxytprogesterone (by 17α-OHase) and then to deoxycortisol, and thereafter to the final product: cortisol (hydrocortisone). Cortisol is the major glucocorticoid in humans, and it is known as the "stress hormone", but it also has other roles such as the metabolism of proteins, fats and also has anti-allergy & anti-inflammatory effects.

If the product is 17α-hydroxpregnenolone, it can get converted to deoxycortisol, or after various steps to androstenedione (the main androgenic precursor to testosterone & dihydrotestosterone in males or estradiol in females or.

There is no glucocorticoid production in the testes; therefore P45017α serves only to produce androgens in the leydig cells (also known as the "interstitial cells"). P45017α consists of two components: the 17a-hydroxylase (17a-OHase) component and the 17,20-lyase component. The 17α-OHase component hydroxylates pregnenolone to 17α-hydroxypregnenolone, and progesterone to 17α-hydroxyprogesterone. The 17,20-lyase component can cleave the carbon bonds at C17 - C20 of 17α-hydroxypregnenolone which leads to the production of the androgen dehydroepiandrosterone (DHEA). In addition, the same cleavage mechanism on 17α-hydroprogesterone yields androstenedione (AD).

Alternatively, DHEA is converted to AD via the enzyme 3β-HSD. AD can then get converted to the major male sex hormone testosterone via 17β-HSD (17β-hydroxysteroid dehydrogenase). Thereafter, the enzyme 5α-SR (5α-steroid reductase) can reduce to testosterone to the more active form; dihydrotesterone. [2, 6]



Figure 3: showing the steroid-biosynthesis pathway. [6]

Role of hormones in Prostate Cancer

The concept of androgen-dependent tumour was first proven in 1941 by Huggins and Hodges [6] (Noble Prize-winning research) with the observation that the removal of testes in males led to a regression of prostate cancer. These observations led to extended studies of the role of hormones in cancer, in both animals and humans.

Evidence suggests that androgens play crucial role for the growth, development and maintenance of prostate cells. It has been proposed, in several studies [11, 12], that androgens play a vital role in the initiation and progression of hormone-dependent prostate cancer. These studies have also shown that prolonged exposure to androgens can be associated with a higher risk of prostate cancer. As seen in Figure 4, the production of androgens starts with the release of leuteinising hormone releasing hormone (LHRH) from the hypothalamus, which stimulates the pituitary gland to release letueinising hormone (LH). LH then travels through the circulatory system and binds to specific receptors on leydig cells in the testes, and thus stimulates the production of testosterone. Testosterone, in turn, binds to plasma albumin or sex hormone binding globulin (SHBG) and therefore can be transported throughout the body. It enters the prostate cells via passive diffusion, where it has been shown to start tumour proliferation, either directly or when it is converted to its more active form, i.e. dihydrotestosterone.

The tumour stimulation is initiated through a series of complex interactions that involves interaction between the hormone binding site and the complex that have arisen during the binding of androgens (testosterone or dihydrotestosterone) and the androgen receptor (AR). The binding initiates transcription, leading to protein synthesis and subsequently to cell division, which could potentially result in an increase in tumour mass. [6]

Figure 4: Showing the androgen-signalling axis. [6]

Treatments of PC

Surgical treaments

Prostatectomy (removal of prostate gland)

Bilateral Orchiectomy (removal of testicles)

Radiation therapy (use high energy radiation to destroy the cancer cells)

Chemotherapy (e.g. paclitaxel, works by stiffening and locking the microtubules leading to cell deaths druing cell division)

Hormonal therapy (LHRH agonist/antagonsts and antiandrogens) [13]


Androgens have a vital role in growth and progression of prostate cancer. Therefore, one of the main targets for the treatment of prostate cancer is to lower androgen levels in the PC cells. Androgens receptor is the target ofantiandrogens. One steroidal and three non-steroidal antiandrogens are used commonly for the treatment of prostate cancer (see Figure 5 for side effects profiles, dosage regimen etc.), either as monotherapy or in combination with LHRH analogues. [13]

Figure 5: showing sides effects and properties of the currently available antiandrogens. [13]C:\Users\Zaid\Desktop\Untitled-1.jpg

Nonsteroidal antiandrogens (bicalutamide, flutamide, nilutamide) competitively inhibit androgens from binding to the androgen receptor (AR). Therefore, the testosterone serum levels are not reduced and can even increase.

Bicalutamide is the most studied nonsteroidal antiandrogen [14]. In two combined randomised trials involving 480 patients with locally advanced non-metastatic disease (clinical stages T3-T4), bicalutamide monotherapy (150 mg daily) was compared to castration. After a median follow-up of 6.3 years, there was no detectable difference concerning time to progression or overall survival [15]. The results showed that patients with a limited tumour load, non-steroidal antiandrogen monotherapy seemed as effective as castration. However, some advantages of bicalutamide monotherapy were observed regarding sexual interest and physical capacity.

In a randomised trial, with 220 patients with stage T3/T4 of PC, using bicalutamide monotherapy (150 mg daily) was compared to combined androgen blockade. Patients in the bicalutamide group underwent castration at disease progression. There were no detectable differences concerning disease-specific or overall survival [16] while subgroup analysis suggested an unexplained increased overall mortality in patients with high-grade disease treated with bicalutamide only [16]. Thus, after adequate patient information, bicalutamide monotherapy is an option for younger and sexually active patients with locally advanced disease and in selected patients with metastatic prostate cancer. [17]

Overall, the currently available data from (McLeod DGs et al) EPC studies suggest that early hormonal therapy is not beneficial in patients with localized disease while prolonging overall survival in patients undergoing primary radiotherapy [18].

Combined androgen blockade (CAB)

Surgical castration or LHRH agonists removes testicular androgens, however, about 5% of the testosterone is still being produced by the adrenals. This would continue to stimulate the growth of the prostatic tumour; therefore the concept of combined androgen therapy emerged. The treatment includes combination of castration or a LHRH agonist with an antiandrogen to counter the action of residual testosterone or DHT on the androgen receptor in PC cells. [13]

There have been many trials to study the effect of the combined androgen blockade. Based on 10 trials with available 5-year survival data, the meta-analysis data showed that there is a significant survival advantage for combined androgen blockade [19]. The data has also shown that combined androgen blockade (using a non-steroidal antiandrogen) tends to delay disease progression better than monotherapy.

However, the limitations of the combined treatment (over monotherapy) must be considered; higher sides effects and costs. The extra cost for one "quality-adjusted life-year" gained with CAB over orchiectomy alone has been estimated to be one million US dollar [Prostate Cancer Trialists' Collaborative Group 2000]. Combined androgen blockade is an option for patients with advanced or metastatic prostate cancer. It is, however, not the standard form of androgen ablative therapy for primary application.


Antiandrogens are a treatment option in some patients with prostate cancer. They are useful in some cases as monotherapy, but sometimes, in advance cases must be used in combination with LHRH analogues or castration. One way that is not used widely, in the steroidal cscade, to block androgen is 5α-reductase inhibitors. Testosterone in peripheral androgen-dependent tissues is converted to the more potent dihydrotestosterone by two isoforms of 5α-reductase, SRD5A1 and SRD5A2. Therefore by inhibiting this enzyme could lead to the inhibit of DHT.