Introduction
Malignancy in salivary gland forms a significant percentage of oral tumors since , it comes after squamous cell carcinoma (SCC).(1) three main paired salivary glands tumors are, sublingual ,parotid, and submandibular salivary glands and several of small salivary glands that present in the sub-mucosa of oral cavity and oropharynx are able of displaying malignancy .(2)
Yearly occurrence of salivary gland tumor all over the world are between 1 to 6.5 each 100,000 persons. They signify 3-5% of neck and head neoplasms. Most of salivary gland cancers occur in parotid gland. Though, 80% of growths are benign and 20% are malignant. (3) In the period between 2002 -2003, 1015 patients of neck and head malignancy attanded National Cancer Institute, Cairo (NCI), Egypt. There was a male prevalence in all types except malignancy of salivary glands. yearly incidence of salivary gland malignancy in Egypt are from 0.3 – 0.4 % of all head and neck malignancy occur in age of 52.5 years.(4) Correspondingly, in Egypt benign tumors represents 48.8% of salivary gland tumors, while malignant tumors represents 31.7% of tumors of salivary gland.(5)
Information about physiological changes happen during tumor initiation and progression is base for preventing, predicting the prognosis of satisfactory treatment of malignancy.(6)
Amongst these tumors , mucoepidermoid carcinoma (MEC) is the most incident . salivary gland Muco-epidermoid cancer was first labelled with Stewart in 1945 , who considered it a separate entity in neoplasms of salivary gland.(7) Prevalence of MEC among salivary gland cancers represent about 12 – 40% universally..(8;9) It arises from reserve cells in excretory channels of salivary glands and comprises of mucous, epidermoid, and intermediate cells.(10) it is classified Histo-pathologically into three grades: low, intermediary, and high grades.(11)
(MEC) Progression requires attainment of some properties that indorse tumor aggressiveness. Recognition of Proteases and protease inhibitors have an essential roles in malignancy invasion and metastasis. Two modules of proteases were widely investigated particularly in breast and other tumors: serine proteases and their inhibitors and metallo-proteinases and their inhibitors.(12;13)
Inhibitor of mammary Serine Protease (MASPIN) is protein with molecular weight of 42 kD (14) and considred one of serine protease inhibitor (SERPIN) family(14;15) , which includes a large group of proteins with diverse biological activities.(16)
MASPIN is a new serine protease inhibitor (SERPIN) with complex tumor inhibition actions. It was initially recognized in normal human breast myo-epithelial cells and displays different expression in various types of malignancy cells. It shows antimetastatic activities in mammary and prostate malignancy, Its expression is retained during pancreatic, ovarian, and lung carcinomas, which indicated that it regulated metastatic potential is tissue selective. Therefore, it is likely that Maspin contributes in salivary gland tumor biology too.(17)
It was discovered that maspin protein is expressed in many kinds of tumors. (18 -22) Most investigators established that increasing of maspin expression related to improving prognosis of those cancers.(23) While, it was noted that maspin over expression is related to bad prognosis in pancreatic, ovarian cancinomas some carcinomas.(24) Though few studies indicated that maspin expression in salivary gland cancers were published.(23)
As, maspin was existing in the epithelium of other glands, it is likely to share in salivary gland biology also.(23) Therefore, the current study will performed to validate, monitoring, and relate the variances of maspin expression in salivary gland muco-epidermoid carcinoma , and related clinical pathological factors.
Review of Literature
Mucoepidermoid carcinoma (MEC) of Salivary gland:
Definition:
muco-epidermoid tumor is a glandular malignant epithelial malignancy that consisted of mucous, intermediate, and epidermoid cells. This tumor can unpredictably encapsulated or infiltrative and show cysts of variable sizes.(25) It was earlier recognized as a muco-epidermoid tumor that involves a benign tumor and potential of a tumor with metastatic.(26) After recognizing its malignancy possibility even in the “benign” group, in 1953 the tumor taught the more suitable term carcinoma of muco-epidermoid.(10)
Epidemiology:
(MEC) of salivary glands is the most incident malignant tumor diagnosed amongst salivary gland tumors after that adenoid cystic carcinoma.(27) it represents 12% of salivary gland tumors(28) and about 35% of all major and minor salivary gland malignancies.(29)
Etiology:
While, MEC etiology is not well identified, high or prolonged doses of radiation to head and neck are revealed as risk factors for salivary gland tumors .(30) Other studies proposed that disclosure to silica, cholesterol rich diets and vegetable depleted can be further risk factors for salivary gland MEC incidence.(30) Moreover, many studies showed that a history of prior cancer, especially those related with ultra violet radiation, immune-suppression and Epstein Barr virus were established to be related to an increased occurrence of it.(31) ,as well as the association with cyto-megalovirus.(32)
Origin and pathogenesis:
MEC supposed to rise from reserve cells in the interlobular and intralobular segments of salivary duct structure, it is a malignant epithelial salivary gland neoplasm comes from epithelium of ductal (33- 34)
It can be rised centrally in the mandible, probably from embryonically trapped salivary elements or from neoplastic transformation of mucous cells in odontogenic cysts.(33)It can also come from middle inside maxilla, probably from neoplastic transformation of maxillary sinus lining or trapped minor salivary glands in maxilla.(35)
Clinical features:
Age
MEC is the most frequent salivary gland tumor in adults and children.(10;36) Low to intermediary histopathologic grade are more frequent than high grade in children.(37) There is a tendency for adults in fourth to sixth decade with the highest occurrence during fifth decade.(38)
Gender
There is a 3:2 female preference (39) that differs according to placeof tumor.(36;40)
Site
Around 53% occur in major glands. Parotid glands predominate, 45%, with 7% for sub-mandibular glands and 1% in sublingual glands.(25) the most common intra oral sites are the palate and buccal mucosa.(41-43) Also, it arises centrally in mandible, probably from embryonically trapped salivary elements or from neoplastic transformation of mucous cells in odontogenic cysts.(33)
Mandible has than in maxilla three fold more frequency than molar – ramus zone.(44) It also rises in base of tongue but its not mutual.(29)
Other sites of MECs
1. Lung: MEC is a very rare malignancy of lung involving <1% of total lung cancers. Low grade MEC has a superior prognosis rate than high grade one.(45)
2. Thyroid gland: Primary thyroid MEC is an infrequent malignancy typically displaying indolent clinical actions, and It comes from squamous metaplasia , Hashimoto thyroiditis, or other neoplastic developments.(46)
3. Maxillary sinus: It arises centrally from neoplastic transformation of the maxillary sinus lining or the trapped minor salivary glands in maxilla.(35)
4. Conjunctiva: It is rare, aggressive variant of SCC. Early intervention is important to inhibit intraocular invasion and systemic metastasis. (48)
5. Skin: (MEC) of skin is a rare neoplasm with few cases stated in researches.(49)
6. Hypoglossal duct remnant: It is reported that MEC arises from thyroglossal duct remnant.(47)
Sign and symptoms
The main symptom is a sluggishly enlarging painless mass for long period clinically imitating a pleomorphic adenoma or other benign neoplasms. Pain or facial nerve palsy develop, frequently in association with high grade tumors. Low grade malignancy is described by a slow growing painless enlargement which rarely exceeds 5 cm, while high-grade malignancies are rapidly growing, painless, infiltrate into adjacent tissues, and are associated with distant metastases and extra-oral ulceration.(50) Minor tumors are asymptomatic, fluctuant and red/blue in appearance. Whereas, all MECs are able to metastases, metastases often arise in high grade lesions. Lesions of metastases are lymph nodes, lungs and bone are typical distant lesions.(51)
Histopathology:
MEC is a neoplastic epithelial salivary gland tumor rising from ductal epithelium(34) and histologically consists of a mix of mucus cells, intermediate cells, and epidermoid cells. MEC was formalized as a distinct entity tumor that may also show clear cell, oncocytic, or columnar cells.(52)
Epidermoid cells found in tiny nests or partially line cystic and duct alike spaces. They may form big polygonal cells among smaller intermediate cells or form islands and strands surrounded by smaller intermediate cells. Keratin pearls and intracellular keratin are infrequently appeared in an swollen cancer.(41)
The intermediate cells are somewhat bigger than lymphocytes, they are present in clusters or large solid layers.(53)
Morphologically mucous epithelial mucin cells can resemble intermediate, epidermoid, clear, columnar or occasionally mucous acinar cells, polygonal shaped cells. They are present in clusters or scattered through other cells or lining cystic places.(54) They normally form less than 10% of tumor. Sialo-mucin content is confirmed by alcian blue staining.(55;56) Many mucoepidermoid carcinoma displays cystic or papillary cystic component and duct like assemblies. The lumen holds mucin. The fibrous stroma is frequently abundant and occasionally hyalinized.(57)
A focal sebaceous and oncocytic discrepancy is sporadically existent. Dedifferentiated component was observed, and also variable quantities of clear cells which have glycogen or mucous.(58;59)
MEC Sclerosing is described by the incidence of wide area of scleroses and excess collagenization while the rest of tumor characteristic of MEC are found at the periphery.(53;60)
Variants and differential diagnosis of MEC:
MEC differs dependent on the percentage of the dominating cell of thetumor. Its variations comprise clear cell, sclerosing cells with or without eosinophilia, unicystic, sebaceous, psammomatous, spindle cell, goblet cell violent, and oncocytic of MEC.(61)
Oncocytic metaplasia rarely was described in MEC. Most salivary gland sites with oncocytic change are benign; so, it is essential to discriminate MEC from other entities that display noticeable oncocytic change.(62)
Sclerosing MEC (SMEC) is very infrequent variant that is the maximum frequent primary malignancy of the salivary glands. Sclerosing MEC (SMEC) is described by an strong central sclerosis that inhabits the entirety of an otherwise typical tumor, frequently with an inflammatory penetrate of plasma cells, eosinophils, and lymphocytes at its peripheral areas, but its un-common with inflammatory cell penetration can clarify its progressive stage of the sclerosis.(63)
Grading:
MEC has 2 subtypes of MEC included a “benign” and “malignant” version which equates to low to high grade, correspondingly. Current practice is to stratify tumors into low (LG-MEC), intermediate (IG-MEC), and high-grade (HG-MEC). The American Forces Institute of Pathology (AFIP) grading system,(16) Brand wein system,(1) and to a minor extent, the modified Healey system(65) are the popular systems employed (Table 1).
AFIP and Brandwein system are point oreinted, ascending point scores to each adverse histologicpathological factors and with ascending point scores associating to a higher grade.
In spite of the long standing accessibility of these grading schema, several pathologists still escape using them, mostly due to their unwieldy nature and the vagueness of every histologic measures.(67)
Actually, in certain cases, this deficiency of user approachability” is not essential. For instance, the Brandwein grading scheme is point based, but, on close investigation it is readily seeming that this grading scheme is simply be summarized as follows: there is a pool of intuitively adverse factors . A tumor with no adverse parameters is low grade, those with 1 bad parameter are intermediate grade, and those with 2 or more bad parameters are high grade.(68) Using this simple algorithm will gives precisely very similar grade as the Brand wein system, and extra fast. In additionall grading systems are effective. However, each grading system differs regarding performance of every certain grade.
The AFIP system appears to down grade tumors while the Brandwein system seems to up-grade tumors.(69) Brandwein system may classify some indolent tumors as high grade, perhaps results to needless radiation or need of surgery.(52)
Therapy intermediate grade cancers is debatable by means of the behavior of intermediate grade cancers differs dramatically in the literature. Astute spectators note that there is one central source of variant is the grading system used. For example, Aro (70) used AFIP system propose that intermediate grade MEC cluster with high grade MEC, and must deal in a similar manner. Conversely,a study indicated that intermediate grade MEC cluster with low grade MEC by usage of Brand wein system. As a histologic associate, morphologic spectrum of intermediate grade cancers differs reliant on the system of grading.
The efficacy of grading as it used to variations of is not clear. Limited evidence to date proposes that even oncocytic MECs that are considered high grade with a conventional grading scheme may act idly, with only 1 recurrence noted.(71) indication is still inadequate to confirm approving discarding grading for these variations.
Radiographic findings:
Assessing salivary gland cancer by magnetic resonance imaging and computed tomography evaluate analogous features, internal homogenicity/ heterogenicity, improvement pattern, extraglandular extension , and incidence of adjacent malignant lesions.(72) Whereas, Ultra-sonographic attendances of MEC as the following, the lesion size of low grade MEC was lesser than those of intermediate and high grade. lesions of the salivary glands were frequently allied with heterogeneous echotexture, indistinct margins, irregular outline, and lack of distal acoustic enhancement. Sometimes, They displayed cystic areas, calcifications, regional lymph node enlargement.(73)
Treatment and prognosis:
Universal clinical factors e.g., stage, age, and margin status remain important prognosticators for MEC.(74;75)
The mean age was lower between patients with a low grade histologically than those with a high grade that are maximum (76). Many reports exposed that patient’s age is one important prognostic factors in MEC (77-79).
Hiroyuki Ozawa (39) stated that, consistent with TNM classification, T -T and N -N describes regional lymph nodes that are involved are substantial prognostic features. T factor, strongly correlated to surgical margin and facial palsy, described as a significant factor of parotid gland cancer.(79) Lymph node metastasis is related to histologic malignancy. A high rate of metastasis was observed in MEC patients with high histopathological grade.(76)
The dimension of the primary cancer or histologic malignancy is reflected to affect distant metastasis.(80) Metastatic lesions from low grade MEC may grow slower than high grade MEC.(81)
The correlation between primary site of mucoepidermoid carcinoma and its prognosis is debated.(80) Although submandibular mucoepidermoid carcinoma was described to have poor prognosis.(82;83) it was described that primary site of MEC has no effect on the overall survival and did not basis a deflection of histologic malignancy.
Histologic factors like, perineural and angiolymphatic invasion are valuable prognostic factors and they are used in grading systems.(74;75)
It is critical to translate the various MEC grades into therapeutically categories as indicated in Table 2.
Patient consequence in various grades of MEC proposes a necessity for overview of the treatment protocol, especially with regard to LG MEC and IMG MEC. The seemingly unusual incidence of locoregional disappointments and metastases in LG MEC proposes a restrictive approach in surgical management. On the other hand, the regular incidence of such failures in IMG MEC warrants an aggressive approach with these cancers.(70)
Parotid gland High grade MEC is a violent disease that commonly found at progressive stage. Parotidectomy with revised radical neck dissection and post-operative XRT offers reasonable local and regional control for patients with N+ {regional lymph node metastasis} disease. Elective selective neck dissection and radiation are considered as T3 and T4 cancers with N0( no tumor cells in regional lymph nodes) status.(84)
Low grade lesions look and act like a benign tumor. High grade tumors display typical malignant features, high occurrence of local recurrence (78%), and humble prognosis (27% – 10 year survival rate). Overall 5 year survival for MEC ranges from 92% to 100% for low grade tumors, 62% to 92% for intermediate grade cancers, and 0% to 43% for high grade cancers.(85)
Maspin
Mammary Serine Protease Inhibitor (MASPIN)is a 42-kDa protein(86) , it is one of serine protease inhibitor family that comprises a large protein family with diverse biological utilities(88). This protein, coded by a gene located on chromosome 18 q21.3(89), that first designated in 1994 as a serpin with tumor oppressive activities.(88)
Since, a member of the serpin family, maspin is catigorized with the ovalbumin serpin (ov serpin) subfamily as MASPIN displays important sequence resemblance to chicken ovalbumin.(90) There are currently thirteen known human ov serpins, counting plasminogen activator inhibitor 2 and squamous cell carcinoma antigens 1 and 2 (SCCA1, SCCA2).(88) Ov serpins reside commonly intracellularly, but several, including maspin, may act extra-cellularly. There is a debate about MASPIN protease inhibition; Sheng et al(91) stated that MASPIN has protease inhibitor activity. On the contrary, Bass et al(92) reported that MASPIN has no protease inhibitor possessions.
Protease inhibition happens via the serpin reactive site loop (RSL) which is the primary functional domain of the serpin family.(88) MASPIN RSL domain possesses unique sequence and structure that unlikely included in protease inhibition.(92) MASPIN is presently categorized as a non inhibitory serpin as there are no identified target proteases for MASPIN.(88)
Maspin localization:
Serpins are expressed universally through the body. Expression of MASPIN was verified in multiple tissues like, epithelium of breast, lung, prostate, and epidermis and in stromal cells of the cornea.(93-95) MASPIN proves broad localization patterns(88). In mammary epithelial cells, MASPIN focusses primarily to cytoplasm, but it also present in the nucleus, cell surface and secretory vesicles.(96)
Maspin regulation:
One of controlling mechanisms recognized for MASPIN includ p53 signaling. P53 is a well-known tumor inhibitor that doings as a cell cycle regulatory protein and also plays roles in angiogenesis and apoptosis .(88) It was revealed that adenoviral delivery of wild type p53 to breast and prostate malignance cell lines may prompt expression of MASPIN.(97) MASPIN regulation with p53 can clarify role of p 53 in cell invasion and metastasis and hypothesizes that tumor cells expressing mutant p 53 are more probable to metastasize, in part because of the inability to up-regulating the gene of MASPIN.(88)
To demonstrate that maspin was specially induced thru p 53, DU145 cells infected with adenovirus vectors expressing p 21 or p 27 were examined for expression of maspin. P 21 and p 27 were highly expressed but did not induce detectable maspin expression. P 53 ,only motivated maspin expression, which proposed that maspin expression was specifically prompted with p 53.(97)
MASPIN and cell motility, invasion, metastasis and angiogenesis:
MASPIN has suppressive effect on tumor-induced angiogenesis (100-102), motility of the cell, invasion and metastasis.(103-105) Invasion and metastasis are biological hallmarks of neoplasms. They induce cancer related morbidity and mortality. Since, it is well known, human tissues are organized into a series of compartments separated from each other thru two kinds of extracellular matrix : basement membrane and interstitial connective tissue. While organized differently, each of these components of the ECM is composed of collagens, glycoproteins and proteoglycans. The neoplastic cells must interact with the ECM at several stages of the metastatic cascade. A carcinoma first must breach the underlying basement membrane, then traverse the interstitial connective tissue and ultimately gain access to the circulation by infiltrating vascular basement membrane to promte secondary growth at a distant lesions.(106) Studies were performed to determine the mechanisms of maspin to give the anti-metastatic effects.(88)
MDA-MB-435 breast cancer cells treatment with recombinant MASPIN (rMaspin) caused increasing of levels of α 5 and α 3 containing integrins. These variations to the cellular integrin profile were accompanied by increased adherence to fibronectin.(88) Integrins are a family of membrane glycoproteins that can attach to a range of molecules present in the extracellular matrix and that can mediate adhesion between a cell and ECM proteins e.g., fibronectin, laminin and collagen. The binding of integrins to ECM ligands prompts integrin clustering and subsequent recruitment of actin filaments and signaling proteins to the integrin cytoplasmic domain. These large trans-membrane adhesion complexes composed of the ECM and intracellular signaling components are called focal adhesion plaques (FAP) which assure cell adhesion to the ECM.(107) In support of a cell surface event, it has been reported that cell surface associated MASPIN is primarily accountable for the antiinvasive behaviours.(108)
MASPIN change the cell integrin profile, maspin re-expression also alters signaling pathways involved in motility and invasion.(88) Treatment with rMaspin resulted in decreased Rac1 activity.(109) Rac1 is one member of Rho guanosine triphosphatase (GTPase) family of proteins which is known to pl ay a role in controlling cell migration..(110) The Rho GTPase family are small GTP binding proteins that comprise RhoA, Rac 1 and cell division control protein 42 (cdc 42). Rho proteins can interact with multiple effectors to activate a complex array of signaling pathways. Rac1 motivates serine – threonine kinase p 21 activated kinase.(109)
Additional anti invasive mechanism supposedly in MASPIN targets urokinase plasminogen activator (uPA) / urokinase plasminogen activator receptor complex on the surface of cells. uPA- uPAR complex is included in conversion of plasminogen to plasmin, an active protease with wide specificity that is able to slice many of extra-cellular matrix proteins such as fibronectin, fibrin and laminin.(88) Plasmin is directly destroy non-fibrillar ECM proteins or indirectly destroy fibrillar ECM proteins through stimulating members in matrix metalloproteinase family.(111;112) while MASPIN does not directly supress uPA activity, MASPIN decrease cell surface associated uPA/uPAR by prompting its internalization.(113;114)
Cell surface associated uPA/uPAR complex may stimulate extracellular signal regulated kinase 1 and 2 (115), a importance of it is the transactivation of activator protein-1(AP-1) genes involving uPA and uPAR(116). Therefore, a positive feedback regulation of uPA and uPAR transcription by cell surface uPA/uPAR is involved. If the suppression and depletion of cell surface uPA/uPAR complex by maspin may extra down regulate uPA and uPAR expression.(117)
Role of MASPIN in angiogenesis:
carcinomas don not expand over 1-2 mm in diameter or thickness except they are vascularized. 1-2 mm zone signifies the greatest distance across which oxygen and nutrients inter from blood vessels. Exceeding this size, neoplasm can not increase with no vascularization since hypoxia prompts apoptosis . Angiogenesis is essential not only for continual neoplasm growth but also for metastasis. It is now obvious that mamlignant cells not only yield angiogenic factors but also prompt anti-angiogenic elements and the neoplastic growth is regulated by the equilibrium between angiogenic and anti-angiogenic elements.(106)
Some investigations designated that MASPIN can act as angiogenesis suppressor. rMaspin and secreted suppressor can obstruct the movement of cultured endothelial cells to bFGF and VEGF that functin as important chemo attractants thru angiogenesis. In addition, suppressor was effectivly block neovascularization and decrease density of the neoplasm associated micro-vessels (118;119) also, it was reported that malignancies with both cytoplasmic and nuclear maspin expression had lower VEGF and cyclooxygenase-2 expression than neoplasms with cytoplasmic MASPIN expression only, so inhibition of VEGF by mediated can happen via mediated COX-2 path.
Cyclooxygenase-2, aslo known as prostaglandin endoperoxidase synthase, is a key regulatory enzyme in the prostaglandin synthetic pathway.(121) Production of Prostaglandin cuases increasing of VEGF production.(122) COX-2 over expression is found in numerous malignancies and has been exposed to help in t neoplasm progression by initiation of neoangiogenesis.(123)
Role of MASPIN in apoptosis:
As well as its anti angiogenic possessions, MASPIN also concerned in apoptosis.(88) It was established that maspin sensitizes breast cancer cells to staurosporine (STS) inducing apoptosis.(124) Staurosporine is a synthetic chemical inducing apoptosis thru an intrinsic pathway(125). Maspin sensitizes breast cancer cells to staurosporine induced apoptosis with regulating Bcl-2 family proteins that in turn result in altering of the mitochondrial membrane permeability.(125;126)
Cellular, molecular and biochemical researches confirmed an important role of Bax in pro-apoptotic influence of MASPIN. First, Bax was up regulated in maspin transfected prostate and breast neoplastic cells, while levels of other Bcl-2 family members including Bcl-2 and Bcl-xl, remained unaffected. Second, on apoptosis stimulation, a more quantity of Bax was trans located from cytosol to mitochondria in maspin transfected cells. Third, apoptosis induction of MASPIN -transfected cells was associated with increased activation of both caspase-8 and caspase-9.(127) The apoptotic effect of MASPIN seems to be tumor specific as normal epithelial cells that express MASPIN at a high level are not sensitized to drug induced apoptosis.(128) Prominently, intracellular MASPIN, but not secreted MASPIN, was essential to sensitize breast cancer cells to staurosporine induced apoptosis.(124)
Identification of MASPIN Interrelating Proteins:
several putative MASPIN binding proteins are attached with pathways included in response to cellular strain. These proteins portray MASPIN as an important controller of the cellular stress reaction and propose that maspin may integrate multiple controlling mechanisms such as transcriptional regulation and direct association with stress response mechanisms(88). For instance, one discovery was the documentation of two enzymes of the glutathione (GSH) reduction oxidation system, glutathione S transferase (GST)(129) and glutathione peroxidase (GPX) as reputed MASPIN interacting proteins.(88) GSH redox system is important for keeping cellular integrity and preventing oxidative damage and were concerned in numerous diseases comprising tumor.(130)
interacting GST GPX, and MASPIN have an essential role in controlling glutathione redox reaction, which in turn protects against oxidation-induced damage. Increasing of GST activity, MASPIN decrease the quantity of reactive oxygen species (ROS) produced following oxidative stress. Since , ROS production is related to hypoxia induced angiogenesis, MASPIN directive of GST may offer another mechanism for its anti angiogenic possessions. So, maspin’s interactions with GST and GPX that controlling of the glutathione redox system is a important element of MASPIN job.(88)
Microarray analysis was used as a discovery tool to identify possible cellular pathways that are controlled by maspin. It was originate that maspin re-expression produced by gene repression. Amongst those genes that were down regulated are a number of genes included in the inflammatory reaction. These comprise interleukin-1 α (IL-1α), IL-6, chemokine ligand 20 and chemokine (c-x-c motif) ligand 2 (CXCL2).(88) IL-1α is a pleiotropic cytokine included in inflammatory and immune reactions and are also involved in cancer cell proliferation.(132) Both CCL20 and CXCL2 are chemokines involved in the inflammatory response.(88) Remarkably, CXCL2 is recognized to bind plasminogen and may help in heightened local plasmin formation when linked with the cell surface (133), providing another mechanism for MASPIN to control plasmin formation. MASPIN has anti inflammation activities and provides new vision of MASPIN may exert its tumor inhibition impacts.(88)
Decreasing in MASPIN is related to poor prognosis in various malignancy such as ovarian cancer, oral squamous cell carcinoma, lung and prostate cancer.(120;134-137)
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