Up-regulation of CD40 with juxtacrine activity in human nonsmall lung cancer cells correlates with poor prognosis

Cancer. 2008 Aug 1;113(3):530-41. doi: 10.1002/cncr.23618.


Background: CD40 and its ligand, CD154, play a regulatory role in several signaling pathways among lymphocytes. Recently, it was reported that CD40 is expressed in several malignant tumors. However, the clinical impact of CD40 expression in nonsmall cell lung cancer has not been studied widely.

Methods: One hundred twenty-nine surgical specimens of nonsmall cell lung cancer were assessed immunohistochemically for CD40 and CD154 expression, and that expression was correlated with patients' clinicopathologic parameters and outcome. Subsequently, in vitro analysis of CD40-CD154 signaling was performed.

Results: Immunohistochemical staining of tumor cells confirmed that 67 patients (51.9%) were positive for CD40, and 76 patients (58.9%) were positive for CD154. The survival of patients who had tumors that were negative for CD40 was significantly better than the survival of patients who had tumors that were positive for CD40 (P = .0004). Multivariate analysis using a Cox regression model indicated that CD40 expression in cancer cells is an independent, unfavorable prognostic factor (risk ratio, 1.855; P = .0403). By using an in vitro juxtacrine growth factor assay, the growth of LK2 cells (CD40-positive/CD154-negative) was accelerated by CD154-positive cancer cells, such as PC10 cells (CD40-negative/CD154-positive), by a juxtacrine mechanism.

Conclusions: The current results suggested that CD40 expression in tumors is associated with a poor prognosis and that the juxtacrine interaction of CD40-CD154 among cancer cells facilitates the development of malignant potential in nonsmall cell lung cancer.

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Animals
  • CD40 Antigens / genetics*
  • CD40 Antigens / metabolism*
  • CD40 Ligand / genetics
  • CD40 Ligand / metabolism
  • Carcinoma, Non-Small-Cell Lung / diagnosis*
  • Carcinoma, Non-Small-Cell Lung / genetics
  • Carcinoma, Non-Small-Cell Lung / metabolism
  • Carcinoma, Non-Small-Cell Lung / mortality
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Lung Neoplasms / diagnosis*
  • Lung Neoplasms / genetics
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / mortality
  • Male
  • Mice
  • Mice, SCID
  • Middle Aged
  • Paracrine Communication* / genetics
  • Paracrine Communication* / physiology
  • Prognosis
  • Survival Analysis
  • Transplantation, Heterologous
  • Tumor Cells, Cultured
  • Up-Regulation


  • CD40 Antigens
  • CD40 Ligand