Tumour Review
Evolving role of uPA/uPAR system in human cancers

https://doi.org/10.1016/j.ctrv.2007.10.005Get rights and content

Summary

Recent advancements in cancer research have led to some major breakthroughs; however, the impact on overall cancer-related death rate remains unacceptable, suggesting that further insight into tumor markers and development of targeted therapies is urgently needed. The urokinase plasminogen activator (uPA) system represents a family of serine proteases that are involved in the degradation of basement membrane and the extracellular matrix, leading to tumor cell invasion and metastasis. In this review, we have provided an overview of emerging data, from basic research as well as clinical studies, highlighting the evolving role of uPA/uPAR system in tumor progression. It is currently believed that the expression and activation of uPA plays an important role in tumorigenicity, and high endogenous levels of uPA and uPAR are associated with advanced metastatic cancers. The endogenous inhibitors of this system, PAI-1 and PAI-2, regulate uPA–uPAR activity by either direct inhibition or affecting cell surface expression and internalization. PAI-1’s role in cancers is rather unusual; on one hand, it inhibits uPA–uPAR leading to inhibition of invasion and metastasis and on the other it has been reported to facilitate tumor growth and angiogenesis. Individual components of uPA/uPAR system are reported to be differentially expressed in cancer tissues compared to normal tissues and, thus, have the potential to be developed as prognostic and/or therapeutic targets. Therefore, this system represents a highly attractive target that warrants further in-depth studies. Such studies are likely to contribute towards the development of molecularly-driven targeted therapies in the near future.

Introduction

Cancer remains one of the deadliest killers of our time, responsible for millions of deaths annually around the world. Approximately half of those deaths could have been prevented with new and innovative pre-diagnostic screening and treatment tools.1 Unfortunately, with the current number of different types of cancer at approximately 210 and new mutations appearing frequently, scientists are still on the search for the holy grail of effective cancer treatments. A better understanding of molecular events defining the physiological progress of cancer is crucial towards the ultimate goal of designing new and effective therapies. The urokinase plasminogen activator system, universal to all cancers, is a serine protease family comprising of urokinase-type plasminogen activator (uPA), plasminogen activator inhibitors (PAI’s), tissue-type plasminogen activator (tPA) and the uPA receptor (uPAR). The urokinase plasminogen system is particularly associated with the process of metastasis, the spread of primary tumors to distant organs which is always associated with poor prognosis and high mortality. In this article, we examine the relationship of the urokinase plasminogen system with numerous cancers to showcase the system’s relationships with some of the most common and some of the rarest cancers today.

Section snippets

The urokinase plasminogen activator system

The urokinase plasminogen activator system provides the most substantial amount of activated plasminogen when tissues are being degraded.2 However, different components of the system are located in different areas based on the type of cancer. uPA system is primarily associated with the degradation and regeneration of the basement membrane and extracellular matrix that leads to metastasis. uPA also aids in anti-thrombolytic activities to remove blood clots and helps stimulate angiogenesis in

Esophageal cancer

With an estimated 15,560 new cases and 13,940 deaths in 2007,37 esophageal cancer remains a serious cancer threat. In a study, uPA, uPAR and PAI-2 were examined in 56 patients with esophagectomies using immunohistochemistry and in situ hybridization to examine how these proteins are distributed in tumors.38 Esophageal cancer was chosen because it has one of the lowest survival rates of cancers. Researchers found that uPA, uPAR, and PAI-2 were not seen at all in normal esophageal tissues. uPAR

Gastric cancer

Gastric cancer is one of the rarer forms of cancer, accompanied by a very low cure rate and very high mortality rate. Searching for a diagnostic tool specific to gastric cancer, MMP-2 mRNA expression was investigated using RT-PCR, and uPA and uPAR mRNA using Northern Blots, in 67 tumor samples.39 uPA and uPAR levels were both found to be statistically greater in gastric cancer tissues. Also, tissues with high amounts of uPA/uPAR expression were correlated with high mortality, with the mean

Colorectal cancer

Colorectal cancer is one of the widely occurring cancer types globally. A retrospective study tested the relationship between preoperative plasma levels of soluble form of uPAR (suPAR) and survival in 591 colorectal cancer patients.41 It was reported that higher preoperative levels of suPAR resulted in increased risk of mortality (p < 0.0001). Taking this as a clue, another study42 was designed to confirm the independent prognostic value of suPAR in rectal cancer. This study determined suPAR

Pancreatic cancer

Pancreatic cancer is the fourth leading cause of deaths related to cancer, due to its late diagnosis and fast progression while showing very few signs and symptoms. More than 60% of the patients are diagnosed with pancreatic cancer when the cancer has already metastasized. The 5-year survival rate for such patients is only about 2%. Less than 10% patients are diagnosed with a localized cancer. This cancer, therefore, presents yet another reason why finding a useful screening tool is crucial for

Small cell lung cancer

Small cell lung cancer is the most aggressive form of lung cancer, with patients generally surviving only few months after initial diagnosis as the cancer cells quickly metastasize to the brain and to bone marrow.47 The following study thus indicates yet another situation where the uPA system would help as a diagnostic and screening tool. The study47 focused on the fact that uPAR expression promotes cell survival by stimulating anti-apoptotic pathways. More so, cells with uPAR expression also

Mesothelioma

Not much is known about the involvement of the components of uPA–uPAR system in mesothelioma. An early evidence for the putative role of uPA in mesothelioma was reported by Shetty et al.48 Mesotheliomas arising from the pleural lining of the chest are particularly aggressive and invasive and the research group was interested in evaluating uPA and uPAR in this system based on the available literature linking uPA with promotion of cellular migration and invasion. Cultured human mesothelioma

Osteosarcoma

Osteosarcoma is the most common form of bone tumors, especially in people ages 15–25. It is the sixth most common cancer in children under 15 and accounts for about 35% of all primary bone malignancies. As such, a landmark study was conducted to learn the chronological order of the progression of events revolving around uPA, uPAR, and PAI-1 using an in vivo study that involved UMR 106-01 rodent osteosarcoma cells, which were then placed on the tibias of athymic female nude mice and studied

Chondrosarcoma

Chondrosarcoma, like osteosarcoma, is very rare. Hackel et al. designed a study to explore the urokinase plasminogen activator system to find out how it could benefit patients suffering from chondrosarcoma.50 Specifically, the study focused on the expression of uPA, PAI-1, and tissue type plasminogen activator (tPA) in 10 dedifferentiated chondrosarcomas and 14 conventional chondrosarcomas. Dedifferentiated tumors have two morphologically and physiologically distinct functions, containing a low

Melanoma

Melanoma affects the smallest number of people but causes the most deaths of any skin cancer. In a study conducted on melanoma, PAI-2’s role in basal cell cancer and epidermal differentiation was investigated.12 Using two mouse lines from PAI-2 encoding transgenes that are under the control of the K5 promoter, researchers first injected one dose of 7,12-dimethylbenz(α)anthracene followed by bi-weekly inoculations of 12-O-tetradecanoylphorbol-13-acetate (TPA). Increased amounts of PAI-2 were

Breast cancer

Breast cancer continues to rank as one of the top killers of women. It ranks number one in the estimated new cancers for females in 2007 with an estimation of 178,480 new cases and ranks second in the estimated cancer deaths in females in 2007 with the figure being 40,460 in the United States alone.37 The high mortality rate associated with breast cancer is directly related to its ability to metastasize readily. Little progress seems to being made in the efforts to combat and prevent this

Endometrial cancer

Endometrial cancer is one of the most common gynecologic diseases globally. Like the case with small cell lung cancer, there is not one common and consistent marker that provides early indication of endometrial cancer. And similar to the research done on small cell lung cancer cells, Memarzadeh et al. examined whether uPAR expression could serve as a consistent indication of endometrial cancer.58 While other markers, such as tumor suppressor genes and DNA repair genes, may show a correlation

Cervical cancer

Cervical cancer, formerly classified as one of the formidable killer of American females, continues to be on the decline. However, the problem is not completely eradicated and almost 12,000 women are still diagnosed annually. Specifically examining stage two cervical cancer patients, one study sought to examine the role of uPA and PAI-1 in relation to relapses and prognosis.11 Seventy-two patient tissue sections were examined, with the breakdown as follows: 10 normal cervical tissues, 28

Ovarian cancer

Ovarian cancer is the fifth leading cause of female cancer deaths though its cause is unknown. Because the role of plasminogen activator in ovarian cancer is known for long,59 a study sought to examine the signaling mechanisms and up-regulation that affect uPA expression enhanced by lysophosphatidic acid (LPA).60 Interestingly, LPA could not be found in patients who do not suffer from ovarian cancer though it is made in large quantities in ovarian cancer cell lines. Like uPA, LPA aids in

Prostate cancer

With an estimated 218,890 new cases and 27,050 deaths in the United States alone,37 prostate cancer continues to be one of the deadliest cancers for men. In a study with prostate cancer, the uPA and uPAR systems were evaluated as potential targets for cancer treatment.61 Unfortunately, once prostate cancer begins metastasizing, it becomes incurable. In this study, small hairpin RNAs (shRNAs) was used to test how they would affect uPA and uPAR expression. In PC3 cell lines (the prostate cancer

Kidney cancer

Renal cancer is rarely detected in its early stages, and its cause is unknown. More than 50,000 people are diagnosed with this type of cancer annually. A study sought to investigate the exact roles of uPA, uPAR, and PAI-1 in metastasis by comparing seven types of normal and cancerous kidney tissues.4 The kidney tissues were categorized as normal kidney tissue, kidney cancer tissue with non-cancerous borders, squamous cell carcinoma, transitional cell carcinoma, von Hippel–Lindau tissue,

Von Hippel–Lindau disease

Von Hippel–Lindau (VHL) disease, a rare hereditary multi-system cancer, is associated with a great increase in angiogenesis, as well as hemangioblastomas of the cerebellum, angiomas of the retina, pheochromocytomas, and renal carcincomas. The VHL gene is turned off in von Hippel–Lindau disease, though sometimes the gene is also turned off in renal cancer carcinomas, hemangioblastomas, and colorectal cancer. Since uPA, uPAR, and PAI-1 have been implicated in the processes of angiogenesis and

Gliomas

Approximately 200,000 people are diagnosed with brain cancer annually, with gliomas making up nearly 50% of all brain tumors. Research continues to focus on preventive and prognostic tools. One such study sought to investigate the exact role that urokinase plasminogen activator plays in gliomas.67 Investigators compared the amount of uPA expression and the rate of patient survival. Seventy seven gliomas were studied, which included pilocytic astrocytomas, grade 2 tumors, grade 3 tumors, and

Pheochromocytoma

Pheochromocytoma is a rare cancer that forms at the center of the adrenal gland. In a research study, it was sought to prove that nerve growth factor induces uPAR expression in the PC12 pheochromocytoma cell system and determine whether or not uPAR expression was necessary for nerve growth factor-driven PC12 cell differentiation.6 The researchers were able to conclusively prove that nerve growth factor does, in fact, induce uPAR expression, adding it to a list of other proteins such as nitric

Thyroid cancer

With thyroid cancer still topping the list of most common cancers, researchers continue to focus on battling it. In a study conducted in Denmark, the researchers focused on the expression of truncated forms of the urokinase plasminogen activator receptor, comparing human cancerous thyroid cells to normal thyroid cells.69 They examined three domains of uPAR: domain 1 (D1), domain 2 (D2) and domain 3 (D3) and also examined uPAR’s relationship to vitronectin. TAD-2 cell lines were used from

Leukemia

Leukemia ranks fifth among males and sixth among females in terms of estimated deaths for the year 2007.37 Collectively, more studies have been undertaken in solid tumors to evaluate the role of the components of uPA system and relatively very less is known about their involvement in leukemia. An early study70 with leukemic cells from 37 patients reported elevated mRNA levels and increased uPA activity in patients suffering with acute myeloid leukemia (AML). Another study71 hinted towards the

Conclusion and perspective

uPA system is increasingly being recognized as a candidate target for gene therapy in cancers.73 The reported biological effects of various components of the uPA–uPAR system in different cancer model systems are compiled in Table 1. The factors responsible for making the uPA system such an ideal candidate for gene therapy relate mostly to the central role of this system in the processes of metastasis. uPA, directly or via plasmin formation, leads to the release or activation of angiogenic

Conflict of interest statement

All the authors declare no competing conflict of interest.

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