Acid Phosphatase

Pathophysiology

The acid phosphatase family is generally divided into 2 major groups depending on the presence or absence of a binuclear metal center. The first group, known as metallohydrolases, displays a characteristic purple color due to charge transfer from tyrosine residue to Fe(III); therefore, they are called purple acid phosphatases. These enzymes can also be differentiated from the other acid phosphatases by their insensitivity to tartrate inhibition, which is why they are called tartrate-resistant acid phosphatases.[1][2]

Clinical Significance

Acid Phosphatase as a Marker

Acid phosphatase can be detected normally in blood at levels ≤2 ng/mL. Due to its secretion from different tissues, it is a nonspecific marker and is more valuable in monitoring response to therapy and prognosis than diagnosis. Prostate cancer is one of the most common cancers in men worldwide. A specific form of acid phosphatase, which is sensitive to tartrate inhibition and known as secretory prostatic acid phosphatase, is normally secreted by prostate tissue. However, cancerous prostate tissue tends to overexpress it. Approximately 95% of patients with prostate cancer have high levels of acid phosphatase, especially if metastasized to bones. Therefore, it was once the major serum marker for prostate cancer screening and staging but has recently been replaced by the more specific prostate-specific antigen. Nonetheless, prostatic acid phosphatase is still used in forensic cases, as it is actively released in seminal fluid and can be used to identify seminal fluid in law enforcement cases.[3]

Bone tissue is a dynamic structure that is continuously formed and resorbed in a balanced process. Osteoclasts, the cells responsible for bone resorption, express another acid phosphatase isoform. Indeed, several studies have shown that acid phosphatase is directly involved in bone resorption. Bone acid phosphatase differs from prostatic acid phosphatase in being a tartrate-resistant acid phosphatase. In osteoporosis, the most common bone disease in humans, the resorption/formation balance becomes disrupted in favor of resorption. Several serum markers for bone resorption have been proposed, such as urinary hydroxyproline, total urinary pyridinoline, and bone sialoprotein. Tartrate-resistant acid phosphatase is precise, resistant to hemolysis, and shows minimal day-to-day variability, making it a potential marker for monitoring therapy response, though it is still under development. In addition, agents that inhibit tartrate-resistant acid phosphatases, such as fluoride, have been shown to improve and even reverse osteoporosis cases.[4][5]

Acid phosphatase has also undergone evaluation in malignancies. Hairy cell leukemia is a chronic lymphoproliferative disease in which neoplastic B cells infiltrate the bone marrow, spleen, and blood, leading to splenomegaly, anemia, and recurring infections. Leukemic cells in hairy cell leukemia have an intracytoplasmic tartrate-resistant acid phosphatase enzyme. In most patients, aspirates from blood or bone marrow are testable for the presence of tartrate-resistant acid phosphatase, which is highly sensitive and specific to hairy cell leukemia, aiding in its detection and diagnosis.[6] Furthermore, when metastasizing to bones, several types of malignancies can induce bone resorption through several steps, including higher expression of acid phosphatase. In these cases, acid phosphatase serves as a serological and histological prognostic marker and a tool to monitor treatment response.[7][8] Another clinical entity where acid phosphatase can be useful is Gaucher disease, the most common lysosomal storage disease observed worldwide. Gaucher disease commonly presents with unexplained hepatosplenomegaly and pancytopenia. The disease is treatable through enzyme replacement therapy with glucocerebrosidase. A serum maker known as chitotriosidase is typically used to monitor the disease burden and response to enzyme replacement. However, tartrate-resistant acid phosphatases may be used instead as a marker when it is normal.[9]

Acid Phosphatase as a Therapeutic Target

As noted above, acid phosphatase as a marker has largely been replaced by more sensitive and specific markers. However, in the past decade, it has gained more interest as a target for immunotherapy against cancers. A novel strategy to eliminate cancer cells is through cancer vaccines that stimulate the adaptive immune system (similar to any other vaccine) to target cells with specific antigens expressed on cancerous cells. These antigens can be tumor-specific, exclusively expressed on cancerous cells, or nonspecific antigens expressed on both normal and cancerous cells; however, they are much higher expressed on cancerous cells, such as prostatic acid phosphatase.[10] 

Sipuleucel-T is an immunological agent composed of fusion protein combining prostatic acid phosphatase with granulocyte-macrophage colony-stimulating factor. The process involves extracting the patient's autologous dendritic cells by leukapheresis, which are then loaded with Sipuleucel-T ex vivo and re-infused to the patient. The dendritic cells stimulate T cells to target cells expressing prostatic acid phosphatase. Three pivotal phase 3 placebo-controlled clinical trials showed that administration of sipuleucel-T every 2 weeks for a total of 3 doses in patients with androgen-independent prostate cancer increased the median survival by greater than or equal to 4 months (P=0.01) compared to placebo. Therefore, sipuleucel-T has been approved by the Food and Drug Administration for hormone-refractory metastatic prostate cancer.[11] Moreover, several clinical trials are underway to evaluate the efficacy of sipuleucel-T in earlier stages of prostate cancer and its efficacy when combined with different other chemotherapeutic agents. Other immunotherapeutic strategies targeting prostatic acid phosphatase are also being developed, such as plasmid DNA vaccines encoding prostatic acid phosphatase. Carriers transport these DNA vaccines to their destination in vivo, the antigen-presenting cells, which can induce an immune response. Johnson and his colleagues developed a DNA vaccine for acid phosphatase using attenuated Listeria monocytogenes as a carrier, which selectively infects antigen-presenting cells. Two phase 1 clinical trials and preclinical studies on rodent models have shown promising results, and a randomized placebo-controlled phase 2 clinical trial is currently being conducted to evaluate this vaccine.[12]

Enhancing Healthcare Team Outcomes

Treatment with sipuleucel-T requires coordination from a multidisciplinary team, including an oncologist, a pharmacist, infusion room nurses, and clinic nurses. The process begins with leukapheresis, where the patient's blood is collected. The blood sample then goes to the manufacturing facility, where the harvested antigen-presenting cells are incubated with recombinant prostatic acid phosphatase and granulocyte-macrophage colony-stimulating factor, activating antigen-presenting cells. The activated antigen-presenting cells are then packed and returned to the infusion center, where they are infused into the patient. The approved treatment regimen involves biweekly infusions.

Treatment with sipuleucel-T for 1 month costs approximately $100,000, making it one of the most expensive cancer treatments on the market. Although sipuleucel-T has shown superior efficacy to docetaxel, the cost difference may barely compensate for the added median life; therefore, funding becomes an obstacle. Fortunately, the Centers for Medicare and Medicaid covers sipuleucel-T treatments. Nonetheless, involving financial personnel and social workers in the treatment process may facilitate funding. In addition, exploring equally effective yet less expensive options is certainly warranted to decrease the economic burden on society.[11][13]