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 Table of Contents  
REVIEW
Year : 2019  |  Volume : 5  |  Issue : 3  |  Page : 56-59

Advances on the components of fibrinolytic system in malignant tumors


1 Department of Clinical Medicine, The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China
2 Department of Nursing, School of Nursing, Hubei Polytechnic Institute, Huangshi, China
3 Department of Medical Imagin, The First School of Clinical Medicine, Southern Medical University, Guangzhou, China
4 Department of Hematology, Zhujiang Hospital, Southern Medical University, Guangzhou, China

Date of Submission16-Mar-2019
Date of Acceptance16-Aug-2019
Date of Web Publication30-Sep-2019

Correspondence Address:
Dr. Lan Deng
Department of Hematology, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, Guangdong Province
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ctm.ctm_14_19

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  Abstract 


The major function of fibrinolytic system is to dissolve the fibrins formed by blood coagulation and maintain the balance between blood coagulation and thrombolysis, which plays an important role in maintaining the liquid state of the blood and unclogging the blood vessels. It is a serious problem that malignant tumor does great harm to human life and health. In recent years, more and more studies signified that the fibrinolytic system in malignant tumors, especially adenocarcinoma, plays a major role in its progression, which indicates that the fibrinolytic system is of great significance in the development of malignant tumors. Besides, the fibrinolytic system has also gradually been known and used to diagnose and treat the adenocarcinoma. This article reviews how the fibrinolytic system works in the occurrence of malignant tumor and summarizes the diagnostic method and treatment of adenocarcinoma according to the latest clinical research progress, laying the foundation for further research.

Keywords: Adenocarcinoma, fibrinolytic system, malignant tumors, tissue-type plasminogen activator, urokinase-type plasminogen activator


How to cite this article:
Ge Z, Xu X, Ge Z, Zhou S, Li X, Yao K, Deng L. Advances on the components of fibrinolytic system in malignant tumors. Cancer Transl Med 2019;5:56-9

How to cite this URL:
Ge Z, Xu X, Ge Z, Zhou S, Li X, Yao K, Deng L. Advances on the components of fibrinolytic system in malignant tumors. Cancer Transl Med [serial online] 2019 [cited 2019 Nov 14];5:56-9. Available from: http://www.cancertm.com/text.asp?2019/5/3/56/268227




  Introduction Top


The fibrinolytic system is a multifunctional and multistructured enzyme system, including plasminogen (PLG), plasminogen activator (PA), and plasminogen activator inhibitor (PAI), which can dissolve fibrin (clot) in blood vessel and keep the blood vessel smooth. There are two types of PA: tissue-type PA (t-PA) and urokinase-type PA (u-PA).[1] The ability of solid tumors to grow and metastasize was significantly dependent on the protease system, such as PLG activation system.[2] The fibrinolytic system plays an important role in the occurrence and development of tumors, especially adenocarcinomas (such as lung adenocarcinoma, breast cancer, and gastric adenocarcinoma) by affecting the digestion of extracellular matrix (ECM), the activation of matrix metalloproteinases (MMPs), and the activation of growth factors.[2] In this article, we review the research progress of fibrinolytic system components in the pathogenesis of malignant tumors and their application in the diagnosis and treatment of adenocarcinoma.


  Study on the Pathogenesis of Tumors by the Related Components of Fibrinolytic System Top


The effect of fibrinolytic system on the pathogenesis of adenocarcinoma is mainly manifested in the invasion and metastasis of cancer cells. Studies have shown that some cancer cells can secrete alanine into the blood, which is transformed into glycoprotein by t-PA and u-PA. U-PA has the ability to promote the formation of tumor blood vessels and worsen the disease,[3] while t-PA is the main intravascular activator of fibrinolysis and the ligand of receptor involved in cell signal transduction. Tumor cells can produce t-PA or t-PA receptor (t-PAR) and mediate a series of reactions to accelerate the proliferation of tumor cells.[4] The activity of MMPs and u-PA is easily inhibited by endogenous tissue inhibitors of metalloproteinases (TIMPs) and PAIs, which are specific inhibitors of MMPs and u-PA. The imbalance between protease and their endogenous inhibitors may lead to the degradation or deposition of ECM,[2] thus increasing the invasion and migration of cancer cells.[5] In breast cancer patients, the interaction between t-PA concentration, PAI-1, and tumor tissue is considered to be an important control factor of breast cancer metastasis to some extent.[6] Kim et al. showed that PAI-1 was involved in the early stage of breast cancer, such as ductal carcinoma in situ, and high level of u-PA was associated with lymph node metastasis in invasive ductal carcinoma.[7]

Deep venous thrombosis is one of the main causes of death in cancer patients.[8] Immunohistochemical analysis of 37 gastric adenocarcinoma specimens by Wojtukiewicz et al. showed that t-PA was weakly expressed in the stroma of tumors, while PAI-1 was strongly expressed, which could activate the coagulation process and lead to thrombosis which in turn lead to death of patients.[9] In addition, Razik et al. found that the expression of u-PA, u-PA receptor (u-PAR), PAI-1, and t-PA in tumor cells and peri-intestinal lymph node metastatic cells was higher than that in normal rectal tissues, while the overall survival rate of patients with low and moderate expressions of u-PA and u-PAR was higher than that of patients with high expression of u-PAR.[10]


  Application of Tissue-Type Plasminogen Activator as a Tumor Marker in the Diagnosis of Adenocarcinoma: Pancreatic Cancer as an Example Top


There is a certain concentration of t-PA and u-PA in normal human serum, so whether it is suitable as a tumor marker for the diagnosis of adenocarcinoma has been controversial. Baluka et al. compared the concentration of t-PA in pancreatic ductal adenocarcinoma (PDAC) tissue homogenate with that in chronic pancreatitis tissue homogenate. The results showed that higher concentration of t-PA was observed in pancreatic cancer tissue, suggesting that t-PA may play a potential role in the occurrence and progression of pancreatic cancer, but there was no significant difference in serum t-PA concentration between PDAC patients and chronic pancreatitis patients. T-PA is not a suitable diagnostic marker for pancreatic cancer.[11] Galactose lectin (Gal) is strongly expressed in PDAC cells and appears in the early stage of cancer precursor lesions but does not exist in adjacent normal tissues.[12] Gal has a high affinity for t-PA;[13] therefore, some people call t-PA as nanoparticles when it is integrated with Gal, and it has been proved that t-PA can be used for the detection of early pancreatic cancer.[12] Some scholars believe that t-PA can be a tumor marker of pancreatic cancer when combined with the body's metabolic state, and there may be more ideas based on metabonomics.[14]


  Study on Fibrinolytic System-Related Components in the Treatment of Adenocarcinoma Top


U-PA plays an important role in the invasion and distant metastasis of adenocarcinoma. It has the ability to degrade ECM components, including laminin, fibronectin, and collagen.[15],[16] Activation of extracellular signal-regulated protein kinase (ERK1/2) triggered by Toll-like receptor 2/4 (TLR2/4) on the surface of activated tumor cells participate in the increase of u-PA and its receptor expression, which enhances the mobility and invasiveness of tumor cells;[17] by down-regulating ERK1/2 expression, the invasiveness and metastasis rate of adenocarcinoma can be reduced,[18] to provide a new direction for clinical research and treatment.

Adenocarcinoma of the lung

Daurinol blocked distant metastasis and development of lung cancer and breast cancer by inhibiting the activity of focal adhesion kinase (FAK) and thereby reducing the production of MMP-2, MMP-9, and u-PA.[19]Cinnamomum cassia extract has antioxidant, antiapoptotic, and cell inhibitory effects. Recent studies have shown that it can also inhibit the metastasis of human lung adenocarcinoma cells by inhibiting the phosphorylation of FAK and ERK1/2, indirectly downregulating MMP-2 and u-PA, and inhibiting epithelial–mesenchymal transition (EMT).[16],[20] Similar functions have been observed with casein and rapamycin.[21],[22] Shih et al. showed that myricetin could also reduce the expression of MMP-2 and u-PA by inhibiting ERK1/2 phosphorylation, thus inhibiting the invasion and metastasis of A549 cells in lung adenocarcinoma.[23] At the same time, they also found that alpha-lycopene could inhibit the metastasis of A549 cells in lung adenocarcinoma by inhibiting the phosphoinositide 3-kinase/Akt (PI3K/Akt) or ERK1/2 signaling pathway and inhibiting the activity of u-PA, MMP-2, and MMP-9.[24] In the study conducted on lung adenocarcinoma, Hsieh et al. found that the extract of Rubus idaeus L. expressed similar efficacy.[25]

Studies have shown that nuclear factor-kappa B (NF-kappa B) is a key transcription factor regulating the expression of many chemokines and cytokines. Its activation is associated with angiogenesis, inflammation, and tumor metastasis.[26] It is a dimer transcription factor consisting of homologous or heterodimer or closely related protein composed of p65 and p50. Generally speaking, NF-kappa B exists in the cytoplasm and forms a polyprotein complex with the inhibitor of NF-kappa B (I-kappa B [IKB]). Under stimulation, signal activates I-kappa B Kinase (IKK), which phosphorylates IKB alpha and leads to its ubiquitination and degradation. Viola yedoensis extract effectively inhibits the DNA-binding activity of NF-kappa B in its DNA-binding domain. Inhibition of the activity of NF-kappa B may downregulate the expression of MMP-2 or u-PA and potentially reduce the occurrence, invasion, and metastasis of tumors. It can also be combined with doxorubicin or cisplatin as adjuvant for chemotherapy in patients with advanced lung cancer.[27]

In addition, Bosse et al. carried out quantitative proteomic studies on the secretory proteomes of erlotinib-resistant and erlotinib-sensitive non-small cell lung cancer (NSCLC) cell lines and found that t-PA was also associated with the resistance of NSCLC to tyrosine kinase inhibitors such as erlotinib. Because compared with erlotinib-sensitive NSCLC cells, t-PA in erlotinib-resistant NSCLC cells increased ten times.[28]

Breast cancer

PAI-1 stimulates angiogenesis by directly inhibiting protease.[29],[30] Clinically, elevated PAI-1 levels are associated with poor relapse-free survival and overall survival in breast cancer patients. Previous studies have shown that PAI-1 is an independent prognostic factor for pN0 breast ductal carcinoma.[31] High concentration of PAI-1 was associated with lower survival in breast cancer patients.[29] Ferroni et al. claim that elevated PAI-1 level may be a prognostic indicator of breast cancer,[32] which is consistent with Piotr's study.[33] Lampelj et al. indicated that higher PAI-1 concentrations were usually noted in larger tumors, higher malignant grade, and invasive ductal histological types of breast cancer.[34] Piotr's study suggests that there is a lack of broad understanding of the role of fibrinolytic system balance in breast cancer progression, and more research is needed to determine the true clinical relevance of its observations.[33]

Other related therapeutic studies

Diallyl disulfide (DADS) is one of the main volatile components extracted from garlic, which can be used for cancer prevention and treatment. Nontoxic dose (<10 ug/ml) of DADS can enhance the expression of u-PA and TIMPs by inhibiting the signal pathways of NF-kappa B and PI3K/AKT and change the balance of MMPs/TIMPs to inhibit the metastasis of adenocarcinoma cells at the esophagogastric junction.[35] 3-hydroxy brass inhibits the expression of u-PA and MMP-2 by affecting the effects of EMT and FAK-steroid receptor coactivator on MEK(mitogen/extracellular signal-regulated kinase)/ERK and RhoA/MLC2 pathways, thus reducing the metastasis of osteosarcoma cells.[36] Compared with other stages of the disease, we found that patients with symptomatic multiple myeloma (MM) had higher levels of activation in cancer-associated fibroblasts (CAF) and increased expression of invasive molecules (including u-PA, u-PAR, and MMP). Under the influence of active MM CAF medium, CAF of active MM cells and U266 cell lines exhibited high proliferation and invasiveness, which were affected by the inhibition of u-PAR gene expression. This indicated that stimulation of u-PA/u-PAR system contributed to the activation phenotype and function of CAF during the progression of MM and provided a new theoretical direction for the study of targeted therapy of MM.[37] The use of new anti-u-PAR compounds, including antagonistic peptides and monoclonal antibodies, as well as novel gene silencing methods, has yielded powerful therapeutic strategies for MM, which may effectively target both malignant cells and tumor microenvironment.[38]

Aspirin inhibits the invasion of prostate cancer cells by reducing the activation of NF-kappa B mediated by NF-kappa B kinase-beta and then the expression of u-PA, suggesting that the ability of aspirin to inhibit cell invasion may contribute to the chemical prevention of metastatic prostate cancer.[39] In addition, gemcitabine can induce endoplasmic reticular stress and express u-PA in cancer cells, which may be related to drug resistance of cancer cells.[40]

T-PA can be used for delivery of nano-targeted drugs.[41] Compared with pure t-PA solution, poly (lactide-co-glycolide) nanoparticles encapsulated with t-PA by chitosan (CS) or changed the permeation and dissolution pattern of thrombus in vitro, which was beneficial to thrombolysis. Whether this nanoparticle could be used in the treatment of secondary thrombosis of adenocarcinoma will be studied.[42]


  Expectation Top


The main function of fibrinolytic system is to dissolve fibrin (clot) in blood vessel and keep blood vessel smooth. However, the members of fibrinolytic system are also involved in the occurrence, invasion, and metastasis of malignant tumors. To study the role of the components of fibrinolytic system in pathogenesis, diagnosis and treatment of cancer, especially adenocarcinoma, will be beneficial to the early diagnosis and drug research of adenocarcinoma. In the future, the composition and efficacy of fibrinolytic system will be studied more clearly. Targeted detection of adenocarcinoma with nanotechnology will be a beneficial complement to the existing cancer detection system. The treatment of fibrinolytic system components will be more conducive to improving the prognosis of patients.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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