Research ArticleClinical Studies

The Role of Soluble CD40L Ligand in Human Carcinogenesis

ANASTASIOS ANGELOU, EFSTATHIOS ANTONIOU, NIKOLAOS GARMPIS, CHRISTOS DAMASKOS, STAMATIOS THEOCHARIS and GEORGIOS-ANTONIOS MARGONIS
Anticancer Research May 2018, 38 (5) 3199-3201;

Abstract

Background: The role of CD40/CD40L in carcinogenesis is widely examined. The mechanisms linking the CD40/CD40L system and the soluble form of CD40 ligand (sCD40L) with neoplasia are nowadays a topic of intensive research. CD40L and sCD40L belong to the TNF superfamily and are molecules with a proinflammatory role. A variety of cells express CD40L such as the immune system cells, the endothelial cells and activated platelets. Although many medications such as statins have been shown to reduce sCD40L, it is still debated whether specific treatments targeting the CD40/CD40L system will prove to be effective against carcinogenesis in the near future. Materials and Methods: A comprehensive search of the Pubmed Database was conducted for English-language studies using a list of key words. Results: At diagnosis, serum samples of patients with neoplasia contained higher levels of sCD40L than healthy controls, suggesting that sCD40L may play a predictive role in human carcinogenesis. Conclusion: Patients with neoplasia had higher circulating sCD40L levels and it is likely that sCD40L may have a predictive role. It is still unclear whether sCD40L can be used as a therapeutic target.

It is well known that the CD40/CD40L system, expressed in a variety of cells such as platelets, endothelium and immune cells, is actively involved in human carcinogenesis and may act as a link between inflammation and neoplasia (1, 2). CD40 is a transmembrane protein receptor and its gene is located in chromosome 20 (3). The cells that express CD40, also co-express the CD40L receptor (4). After the interaction of CD40/CD40L, CD40 is activated and the receptor internalizes into the cell. The activated receptor interacts with the tumor necrosis factor receptor and activates signaling pathways leading to nuclear factor-kappa B (5).

Furthermore, platelets are the main source of sCD40L (6). Platelets express CD40L after stimulation with a wide range of platelet activators such as thrombin (7). The activated platelets may be the origin of the inflammation pathway that leads to human carcinogenesis.

Studies in experimental models have shown that CD40L plays a role in inflammation and neoplasia (8, 9). These studies have examined the role of CD40/CD40L interactions in carcinogenesis.

Materials and Methods

A comprehensive search of Pubmed Database was conducted between September and October 2017. The review covered a period from 1994 to 2017. The keywords which were used individually or in combination were: CD40/CD40L, sCD40L, cancer, carcinogenesis, neoplasia.

Results

Pancreatic cancer. Many studies have investigated the role of serum sCD40L as a possible biomarker in pancreatic cancer. Azzariti et al. (10) in a prospective study, evaluated 27 patients diagnosed with pancreatic cancer and treated with chemotherapy. The sCD40L level was measured in serum at first evaluation, and at a second time after chemotherapy. They noticed a reduction in the sCD40L level after 3 months of treatment in patients with a partial response. On the other hand, in patients with progressive disease, the biomarker statistically increased at the same time. This study also showed a correlation between sCD40L and CA19.9.

Another study from Chung et al. (1) measured sCD40L in patients with pancreatic ductal adenocarcinoma and its utility as a biomarker. sCD40L levels measured in serum were significantly higher in the PDAC group than in the chronic pancreatitis group (CP) and control groups. This result indicates serum sCD40L as a probable biomarker for PDAC.

Moreover, He et al. (11) examined CD40 in pancreatic cancer and the inhibitory effect of the recombinant soluble human CD40 ligand (rshCD40L) in pancreatic cancer cell lines. These cases of pancreatic cancer tissues were analyzed for CD40 expression by ELISA. Also, the serum sCD40 levels in patients with pancreatic cancer were examined by ELISA. As the study showed, CD40 expression was significantly higher in pancreatic cancer tissues compared to normal tissues. CD40 expression levels were linked with TNM stage. Also, patients with pancreatic cancer had higher serum sCD40L levels compared to the healthy control group. CD40 expression was found to be increased during development and metastasis of pancreatic cancer cells.

Nasopharyngeal carcinoma. Many studies with undifferentiated nasopharyngeal carcinoma (UNPC) patients have examined the serum levels of soluble CD40-L. Caggiari et al. (12) showed that UNPC patients have higher serum levels of sCD40L (approximately3-fold) than the control group. Another study from Zhao et al. (13) measured serum sCD40L concentration of 312 patients and 312 healthy controls. Serum sCD40L concentrations were higher in patients than in healthy subjects and also correlated with tumor TNM classification. sCD40L seems to be an independent biomarker for 5-year overall survival and disease-free survival. As they concluded, increased plasma sCD40L levels before treatment are associated with shorter survival time.

Lung cancer (LC). The expression of sCD40L in patients with lung cancer and its possible relation with neoplasia have been studied in many studies. Ellsworth et al. (14) examined 141 non-small cell LC patients. Serum sCD40L levels were measured in plasma samples during radiotherapy (RT) and after RT. They observed that sCD40L has a possible clinical importance in NSCLC patients who undergo RT. Roselli et al. (15) in another study measured sCD40L in 120 patients with different stages of lung cancer and in 60 age and sex-matched control subjects. Patients with lung cancer had higher sCD40L levels than control subjects. Also, sCD40L levels were higher in squamous cancer compared with adenocarcinoma.

Gastric cancer. sCD40L in gastric cancer has been measured in many studies. Li et al. (16) showed that sCD40L inhibits gastric cancer cell growth. At the same time, sCD40L possesses the potential to inhibit gastric cancer cell apoptosis. They concluded that the combination of sCD40L and other cytokines can become a new therapeutic strategy against gastric cancer.

Another study from Li et al. (17) measured the expression of CD40 and CD40L in gastric cancer tissue. In this study, they assessed gastric cancer patients and healthy control subjects. Plasma samples were drawn in the morning of the day before surgery for the measurement of peripheral sCD40L. The expression of CD40 in gastric carcinoma subjects was examined by ELISA. The results showed a higher CD40 expression in gastric cancer tissues. Moreover, Qi et al. (18) showed that CD40/CD40L played an important role in gastric cancer cell cultures. They blocked VEGF receptor signal pathway and reduced the survival-promoting effect of CD40L on gastric cancer cells. After an 8-day cell culture, they showed that it would be important to determine whether the cytotoxic potential of CD40 can be applied in gastric cancer therapy.

Ovarian tumors. The concentrations of the CD40/CD40L system and sCD40L have been studied in women with ovarian tumors. Mielczarek-Palacz et al. (19) found increased levels of sCD40L in the serum of women with ovarian tumors as compared to the control group. Serum sCD40/sCD40L ratio was 8 times higher than in control group and they conclude that it may be a useful biomarker in women with ovarian tumors.

Rectal cancer. In a study from the Department of Surgical Oncology of University of Tokyo Hospital Tada et al. (20) showed the possible predictive role of sCD40L in rectal cancer (RC) patients. In this study, blood samples were obtained pre- and post-treatment with chemo-radiotherapy from 35 patients with advanced RC. The pre-CRT levels of sCD40L and the post-CRT levels were significantly associated with the depth of tumor invasion and with venous invasion. A significant decrease in sCD40L, was associated with a favorable response to CRT. The patients in thit study received a total dose of 50 Gy of radiation and 5-FU-based chemotherapy followed by standardized curative resection. Peripheral venous blood samples were obtained before neoadjuvant CRT and 4-6 weeks following completion of CRT, prior to surgery. These data strongly suggest that sCD40L may play a predictive role as a biomarker in rectal cancer.

Discussion

The CD40/CD40L system is implicated in proinflammatory pathways and is expressed in a variety of cells such as immunity cells, the vascular wall and platelets. Multiple effects have been attributed to sCD40L, triggering all together carcinogenesis in correlation with inflammatory pathways. Patients with different cancers exhibit higher circulating sCD40L levels, and it is likely that sCD40L may play a predictive role in the disease. However, a number of questions need to be resolved in this area of research in the coming years. The protocols measuring serum or tissue sCD40L need to be standardized in everyday clinical practice. Moreover, evidence suggests that high sCD40L levels may predict or may serve as a useful biomarker of the disease. However, it is still unclear whether sCD40L can be used as a therapeutic target in carcinogenesis, as circulating sCD40L levels may represent only platelet activation. Therefore, more clinical studies, using standardized methods for measuring sCD40L, are required to enlighten these issues. Although the development of therapeutic strategies specifically targeting CD40/CD40L seems promising, the data have weakened the enthusiasm. The results of large clinical trials would hopefully elucidate the potential use of sCD40L as a reliable biomarker and therapeutic target in cancer treatment.

Conclusion

Patients with neoplasia exhibit higher circulating sCD40L levels, and it is likely that sCD40L may have a predictive value.

Footnotes

  • Conflicts of Interest

    The Authors declare no conflicts of interest.

  • Received March 6, 2018.
  • Revision received March 30, 2018.
  • Accepted April 2, 2018.

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The Role of Soluble CD40L Ligand in Human Carcinogenesis
ANASTASIOS ANGELOU, EFSTATHIOS ANTONIOU, NIKOLAOS GARMPIS, CHRISTOS DAMASKOS, STAMATIOS THEOCHARIS, GEORGIOS-ANTONIOS MARGONIS
Anticancer Research May 2018, 38 (5) 3199-3201;
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