| Objective: Coagulation factor ⅩⅢ subunit A(FⅩⅢ-A)has long been considered as a simple coagulation factor functional subunit.In fact,FⅩⅢ-A is a transglutaminase(TG),involving in multiple pathophysiological processes.The expression of FⅩⅢ-A is significantly upregulated in some types of cancer cells and tumor-associated macrophages(TAMs),which plays a role in tumor growth and metastasis.However,few studies on plasma FⅩⅢ-A in cancer patients have been conducted and have shown contradictory results.The origin and influencing factors of plasma FⅩⅢ-A,as well as the relationship of plasma FⅩⅢ-A with progression and prognosis of malignant tumor are still unknown.The study explored the value of plasma FⅩⅢ-A in evaluation of curative effects and prognosis in malignant solid tumor,to provid a real-time and effective monitoring indicator for clinical evaluation of curative effects and prognosis in malignant solid tumor.Methods:(1)A total of 1147 inpatients with malignant solid tumors who were admitted to the Department of Oncology,The Second Xiangya Hospital,Central South University,between November 2018 and November 2019 were enrolled randomly in the prospective study.We monitored plasma FⅩⅢ-A antigen and coagulation parameters before and during systemic therapy,and collected the hemogram parameters,carcinoembryonic antigen(CEA)and related clinical data of the patients at the same time for analysis.(2)The patients with plasma FⅩⅢ-A<40%were followed up for a 6-month survival curve analysis and the common complications were analyzed.Meanwhile,the characteristics of change in plasma FⅩⅢ-A corresponding to different prognosis were observed and analyzed.(3)The changes of plasma FⅩⅢ-A levels in pre-therapy patients with non-small cell lung cancer(NSCLC)in different pathological types or stages were analyzed.Logistic regression analysis was conducted to analyze the influence of age,gender,pathological types,pathological stages,tumor surgical history within 1 year and treatment methods on abnormal increase of plasma FⅩⅢ-A(FⅩⅢ-A>150%)in post-therapy NSCLC patients.(4)The post-therapy NSCLC patients were divided into FⅩⅢ-A>150% group and FⅩⅢ-A≤150% group,1:1propensity matching score(PSM)was used to match the age,gender,pathological types and pathological stages of the two groups to exclude confound factors.The association of FⅩⅢ-A>150% with progressive disease(PD)of NSCLC patients was analyzed by unconditional multivariable logistic regression.The characteristics of change in plasma FⅩⅢ-A of NSCLC patients with PD was also analyzed.(5)CD206 and CK7 were used to identify M2 TAMs and lung cancer cells,respectively.Immunohistochemistry and immunofluorescence were used to detect the expression of FⅩⅢ-A in cancer tissues of NSCLC patients,and to analyze the relationship between the expression intensity of FⅩⅢ-A and the pathological features of NSCLC.(6)The effects of extracellular FⅩⅢ-A on the growth and migration of lung cancer cells were investigated by treating cultured NSCLC cell line A549 with different concentrations of activated FⅩⅢ-A in vitro.Results:(1)It was found that D-dimer(D2)=1 mg/L was the inflection point for the association between FⅩⅢ-A and D2: FⅩⅢ-A was significantly negatively correlated with D2(r =-0.39,P < 0.01)and FDP(r =-0.40,P < 0.01)in D2 > 1 mg/L but uncorrelated with D2 or FDP in D2 ≤ 1 mg/L,which can be used to distinguish the interference of coagulation disorder on plasma FⅩⅢ-A in patients with malignant solid tumor.(2)We first clarified the background of abnormal changes in plasma FⅩⅢ-A in patients with malignant solid tumors: plasma FⅩⅢ-A levels are positively correlated with CEA levels((r = 0.11,P=0.003).The marked decrease in plasma FⅩⅢ-A(FⅩⅢ-A < 40%)was closely related to coagulation disorders,while the abnormal increase in plasma FⅩⅢ-A(FⅩⅢ-A>150%)was not significantly associated with the change of coagulation and may be derived from tumor tissue and closely related to tumor progression.(3)The survival time was significantly shortened in patients with plasma FⅩⅢ-A<40%(median survival time 4 months),and25% patients died within 1 month.Serosal effusion and coagulation disorders occurred frequently in patients with plasma FⅩⅢ-A<40%.All the patients who died had a marked decrease in plasma FⅩⅢ-A,with an ending FⅩⅢ-A < 40%;however,the plasma FⅩⅢ-A of the surviving patients all bottomed out and rose again.(4)Plasma FⅩⅢ-A was abnormally increased(FⅩⅢ-A > 150%)in post-therapy patients,especially in NSCLC and lung metastasis patients.Lung adenocarcinoma was the main influencing factor for FⅩⅢ-A>150% in NSCLC patients,and the incidence of FⅩⅢ-A>150% in patients with lung adenocarcinoma was 16 times higher than that in patients with squamous carcinoma(OR =15.77,95%CI: 3.77-65.95,P<0.001).When D2≤1 mg/L,plasma FⅩⅢ-A level of pre-therapy NSCLC patients in advanced stages was higher than that in early stages(86.12±23.46% vs 82.19%±10.00%,P = 0.040).(5)The probability of PD within 4 months in FⅩⅢ-A>150%NSCLC group and FⅩⅢ-A≤150% NSCLC group was both significant different before and after PSM(P=0.006,P=0.021).There was a persistent abnormal increase of plasma FⅩⅢ-A in NSCLC with PD.Plasma FⅩⅢ-A>150% proved to be an independent risk factor for PD in NSCLC patients.The risk of disease progression in NSCLC patients with FⅩⅢ-A > 150% was 6 times higher than that of NSCLC patients with FⅩⅢ-A ≤ 150%(OR=5.74,95%CI: 1.20-27.60,P=0.029).In addition,it has also confirmed that activated FⅩⅢ-A significantly promoted the migration of NSCLC cells,and its effect was enhanced with the increase of FⅩⅢ-A concentration.(6)FⅩⅢ-A was mainly expressed in M2 TAMs in tumor stroma of NSCLC.The expression intensity of FⅩⅢ-A in lung cancer tissues was significantly positively correlated with the density of FⅩⅢ-A+M2 TAMs.In addition,FⅩⅢ-A was also expressed in suspected NSCLC cells.Conclusions: Plasma FⅩⅢ-A is a valuable bidirectional monitoring indicator for assessing curative effects and prognosis in malignant solid tumors,especially NSCLC.Abnormal increase of plasma FⅩⅢ-A(FⅩⅢ-A>150%)suggests poor efficacy and disease progression in NSCLC patients.The marked decrease in plasma FⅩⅢ-A(FⅩⅢ-A<40%)is closely related to coagulation disorders and poor prognosis with a short survival time. |
PDF Full Text Request