Coagulation Factor XIII Subunit A Is a Biomarker for Curative Effects and Prognosis in Malignant Solid Tumors, Especially Non-small Cell Lung Cancer

Abstract

BackgroundThe expression of coagulant factor XIII subunit A (FXIII-A) is significantly increased in some types of cancer cells and tumor-associated macrophages (TAMs). However, few studies on plasma FXIII-A in cancer patients have been conducted and have shown contradictory results, so the relationship of plasma FXIII-A with the progression and prognosis of malignant tumors is still unknown. This study explored the association of plasma FXIII-A with a curative effect and the prognosis of patients with malignant solid tumors.MethodsWe monitored plasma FXIII-A before and during systemic therapy and assessed its relationship with the curative effect and prognosis of malignant solid tumors, especially non-small cell lung carcinoma (NSCLC), by propensity-adjusted, multivariable logistic regression analysis and survival curve, in a prospective study of 1147 patients with different types of malignant solid tumors. The influencing factors of plasma FXIII-A were also analyzed.ResultsWe 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 provided a method to find a more realistic plasma FXIII-A level. Plasma FXIII-A was positively correlated with age, platelets, lymphocytes, monocytes and carcinoembryonic antigen (CEA). It was found for the first time that plasma FXIII-A was abnormally significantly increased (FXIII-A > 150%) in post-therapy patients, especially in NSCLC and lung metastasis patients, and the incidence of FXIII-A > 150% in lung adenocarcinoma was 16 times higher than that in lung squamous carcinoma. FXIII-A > 150% proved to be an independent risk factor for disease progression in NSCLC patients (OR=5.74, 95% CI: 1.20-27.60, p = 0.029), predicting poor efficacy. The marked decrease in plasma FXIII-A (FXIII-A < 40%) was related to coagulation disorders and poor prognosis with a short survival time (median survival time of 4 months).ConclusionsPlasma FXIII-A has the potential to be a real-time biomarker with bidirectional indicator effects to assess curative effects and prognosis in malignant solid tumors, especially NSCLC.

Blocking Immune Checkpoint—LAIR1: Disrupting the LAIR1—FXIII-A—Collagen Immunosuppressive Circuit for Enhanced Antitumor Therapeutics

“…Previous reports showed that in lung squamous cancer, there was a notable infiltration of M2-like TAM exhibiting high FXIII-A expression, which was associated with decreased survival (64). Both mRNA and protein levels of FXIII-A were significantly elevated in M2-like TAM, suggesting FXIII-A may serve as a marker for M2-like TAM, which are a primary cellular source responsible for the abnormal elevation of plasma FXIII-A in patients with malignant solid tumors (65). The role of FXIII-A has been extensively studied in the context of wound healing, where it has been demonstrated to facilitate the cross-linking of fibronectin to collagen and to promote collagen proliferation (39)(40)(41).…”

Transglutaminases are oncogenic biomarkers in human cancers and therapeutic targeting of TGM2 blocks chemoresistance and macrophage infiltration in pancreatic cancer

“…TGM1 was also upregulated in tumor cell aggregates (spheroids) exhibiting low chemosensitivity in ovarian cancer peritoneal uid (43). F13A1 has been identi ed as biomarkers of dismal prognosis in various types of cancers (35,44,45) and promotes the metastasis of melanoma as well as lung squamous cell carcinoma(46, 47). As a well-characterized transamidase, TGM2 can not only promote protein cross-linking by catalyzing post-translational modi cations of proteins, but also function as a G-protein coupled membrane receptor (GTPase), deamidase, adapter/scaffold, protein disul de isomerase, isopeptidase, and kinase (24,(48)(49)(50)(51)(52).…”