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

Abstract

Background: The 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.

Methods: We 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.

Results: We 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).

Conclusions: Plasma 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.

Keywords: biomarker; curative effect; factor XIII subunit A; factor XIII/transglutaminases; non-small cell lung cancer; prognosis; tumor-associated macrophages (TAMs).

Figure 1

Distribution, association and monitoring of the plasma FXIII-A levels in cancer patients. (A) Plasma FXIII-A levels in pre-therapy patients with malignant solid tumors; (B) Plasma FXIII-A levels in post-therapy patients with malignant solid tumors; FXIII-A > 150% was found only in the post-therapy patients, the incidence of FXIII-A > 150% in lung cancer is the highest, the incidence of FXIII-A < 40% was not specific for neoplasm types and occurred both in pre- and post-therapy. (C) The scatter graph with trend line based on plasma FXIII-A level and D2 level in patients with malignant solid tumors; D2 = 1 mg/L is the inflection point for the correlation between FXIII-A and D2. (D) The monitoring of plasma FXIII-A in 13 NSCLC patients with PD. A persistent increase in plasma FXIII-A in all the patients, the plasma FXIII-A level in 9 patients (patient ID: 1-9) lasted over 150% for more than two test times (two courses of treatment). (E) The monitoring of plasma FXIII-A levels in the patients with FXIII-A < 40%. Ten patients ((patient ID: 1-10) who died within four months had a marked decrease in plasma FXIII-A, and with an ending FXIII-A < 40%. The plasma FXIII-A of the surviving patients (patient ID: 11-15) all bottomed out and rose again. (F) Survival curve of the patients with FXIII-A < 40%, median survival time is four months.

Figure 2

The changes in plasma FXIII-A levels in patients with malignant solid tumors during treatment. The abscissa is the corresponding times of treatments n(t) at each test of plasma FXIII-A in patients with malignant solid tumor. For patients with malignant solid tumors that had been treated in another hospital, the times of tests before the first treatment in our hospital was identified as 0.5 times. FXIII-A > 150% was found only in the post-therapy patients, FXIII-A < 40% occurred both in pre- and post-therapy patients.

Figure 3

Flow chart of research steps.

Figure 4

The increase of FXIII-A level promotes NSCLC progression and lung metastasis. Plasma FXIII-A level in some post-therapy NSCLC and lung metastasis patients were significant increase. Lung is an organ with considerable hematopoietic potential, produce numbers of platelets. Platelets, macrophages, monocytes and lymphocytes might be the sources of plasma FXIII-A in cancer patients, and M2 TAMs might be responsible for the abnormal increase of plasma FXIII-A. The expression of FXIII-A is significantly upregulated in M2 TAMs. Numbers of macrophages migrate to the lung in cancer patients. The increase of FXIII-A level promotes growth and metastasis of malignant tumor.