CD40 expression on human lung cancer correlates with metastatic spread

Sabel, Michael S.; Yamada, Makoto; Kawaguchi, Yoshihiro; Chen, Fang-An; Takita, Hiroshi; Bankert, Richard B.

doi:10.1007/s002620050608

Cited by 52 publications

(30 citation statements)

References 16 publications

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“…14 A positive correlation between CD40 expression and metastatic spread has been also reported for human lung cancer. 26 Our results suggest that CD40 -CD154 interaction is relevant for growth and progression of renal carcinomas.…”

Section: Discussionmentioning

confidence: 63%

Expression of CD154 on renal cell carcinomas and effect on cell proliferation, motility and platelet‐activating factor synthesis

Bussolati

Russo

Deambrosis

et al. 2002

Intl Journal of Cancer

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CD40 activation by CD154 may trigger diverse cellular responses, ranging from proliferation and differentiation to growth suppression and cell death, in normal and malignant cells. However, the pathophysiologic role of CD154 expressed by tumor cells remains unclear. We have investigated the expression of the CD40-CD154 system in 24 primary cultures derived from renal cell carcinomas, its correlation with tumor stage and its potential functional significance. We found coexpression of CD40 and CD154 in most of the renal carcinoma cell lines. CD154, but not CD40 expression, significantly correlated with tumor stage. Moreover, renal carcinoma cell lines also released the soluble form of CD154 into the supernatant. CD40 engagement by CD154 did not affect apoptosis or survival. On the contrary, CD154 stimulated cell proliferation, motility and production of PAF, a phospholipid mediator of inflammation with angiogenic properties. Key words: CD154; platelet-activating factor; renal carcinoma; CD40; angiogenesis CD154, the ligand of CD40, is a type II integral membrane protein, related to TNF and FasL. 1 Its receptor, CD40, is a 50 kDa transmembrane glycoprotein of the TNF superfamily, which is expressed in a multitude of different cell types, including B cells, monocytes, dendritic cells, endothelial cells, fibroblasts and renal epithelial cells. 2,3 CD40 was originally identified in a bladder carcinoma cell line, 4 and it is also expressed in a number of carcinomas, such as ovarian, nasopharyngeal, bladder, lung, colon and breast carcinomas, whereas normal nonproliferating tissues are CD40-negative. 5 CD40 engagement by CD154 conveys signals regulating diverse cellular responses, ranging from proliferation and differentiation to growth suppression and apoptosis. 6,7 The CD40 cytoplasmic C terminus lacks intrinsic kinase activity and adapter proteins of the TRAF family appear to mediate the activation of CD40-signaling cascades. 8 Despite the large interest, the functional role of CD40 in cancer development remains undetermined. CD40 appears to possess an opposite effect on tumor cell survival and apoptosis. CD40-mediated signaling has been reported to induce apoptosis when expressed in certain transformed cells of mesenchymal origin 9 and in carcinomas of the breast and lung. 10,11 Conversely, Jakobson et al. 12 demonstrated that CD40 stimulation inhibits Fas-mediated apoptosis in human bladder carcinoma cells and we showed a similar protective effect of CD40 in Kaposi's sarcoma cells. 13 Moreover, immunohistochemic studies revealed that detection of CD40 in primary cutaneous malignant melanoma might have negative prognostic value, suggesting its role in tumor progression. 14 CD154 is coexpressed with CD40 in melanoma cells and some carcinomas. 10,11,14 However, the pathophysiologic role of CD40 -CD154 interaction within the tumor cell remains unclear.In the present study, we investigated expression of the CD40 -CD154 system in 24 primary cultures derived from renal clear cell carcinomas, its correlation with tumor st...

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Section: Discussionmentioning

confidence: 63%

Expression of CD154 on renal cell carcinomas and effect on cell proliferation, motility and platelet‐activating factor synthesis

Bussolati

Russo

Deambrosis

et al. 2002

Intl Journal of Cancer

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“…Also, CD40 was found to be highly expressed in the tumor blood vessels of kidney and breast cancers, suggesting a role of CD40 in the angiogenesis of cancers (24). Sabel et al reported the expression of CD40 in lung cancer tissues was associated with the distal metastasis and poor prognosis of lung cancer (25). In the study, 78% of the cell lines from the patient were found to be CD40-positive and all of these patients were encountered with local or distal metastasis, while cell lines negative for CD40 were all from tumors in stage I, and these patients showed no signs of local or distal metastasis.…”

Section: Discussionmentioning

confidence: 99%

Expression of the co-signaling molecules CD40-CD40L and their growth inhibitory effect on pancreatic cancer in vitro

Zhao

Fei

et al. 2012

Oncol Rep

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Abstract. We investigated the expression of the co-signalling molecule CD40 in pancreatic cancer and the growth inhibitory effect of the recombinant soluble human CD40 ligand (rshCD40L) in pancreatic cancer cell lines. Twenty-six cases of pancreatic cancer tissues and corresponding paratumoral normal tissues were immunohistochemically analyzed for CD40 expression. The association of CD40 expression with clinicopathological parameters, including clinical stage, pathological grade, invasion and metastasis, were statistically analyzed. The serum sCD40 levels in pancreatic cancer patients were examined by ELISA. The expression of CD40 in the pancreatic cancer cell lines Panc-1, Aspc-1 and Miapaca-2 was examined by RT-PCR and flow cytometry. The growth inhibitory activity of rshCD40L on pancreatic cancer cell lines was determined by MTT assay. Tumor cell apoptosis was detected by TUNEL and Annexin V/ PI double staining method. CD40 was positive both on the membrane and in the cytoplasm of tumor cells, 69.2% (18/26) of the cases were positive for CD40. CD40 expression was significantly higher in pancreatic cancer tissues compared to adjacent normal tissues (P<0.05). High CD40 expression was associated with TNM stage and lymph node metastasis (both P<0.05). Patients with pancreatic cancer have higher serum sCD40L levels (3.53±0.70 ng/ml) compared to healthy subjects (1.81±0.48 ng/ml, P<0.05). rshCD40L significantly inhibited the proliferation of the pancreatic cancer cell lines and induced apoptosis in these cell lines. The co-signaling molecule CD40 is highly expressed in pancreatic cancer tissues and cell lines and rshCD40L is a potential tool for antitumor therapies.

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“…Moreover, sP-selectin correlated strongly with both F1 ϩ 2 and TATc levels. Although it is conceivable to hypothesize that a procoagulant activity released from lung cancer cells might stimulate platelet activation and the release of sCD40L, we should also consider the possibility that platelet-released sCD40L may engage interactions with other cell types expressing CD40, including tumor-associated monocytes/macrophages and lung cancer cells (1,24). This hypothesis is in agreement with the findings by Amirkhosravi et al (6), who suggested recently that CD40/CD40L interaction through tumor cell CD40 and platelet CD40L may potentially promote clotting activation by enhancing TF expression on A375 human melanoma cells.…”

Section: Discussionmentioning

confidence: 99%

Soluble CD40 Ligand Plasma Levels in Lung Cancer

Roselli¹,

Mineo

Basili³

et al. 2004

Clinical Cancer Research

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Purpose: Tumor-induced platelet activation may cause the release of various cytokines, including CD40 ligand (CD40L). Activation of the CD40/CD40L pathway in human tumors may result in thrombin generation, which is known to be involved in angiogenesis. Thus, we investigated whether soluble (s)CD40L levels are increased in patients with lung cancer as a result of platelet and/or coagulation activation.Experimental Design: Citrated plasma samples were obtained from 120 patients with different stages and histotypes of lung cancer and 60 age-and sex-matched control subjects. sCD40L, sP-selectin (marker of platelet activation), prothrombin fragment 1 ؉ 2, and thrombin-antithrombin III complex levels (both markers of coagulative activation) were measured in all samples.Results: Patients with lung cancer had median sCD40L levels higher than in control subjects (0.46 versus 0.13 ng/ml; P < 0.0001), although correlation with the stage of disease was not evident. Nonetheless, sCD40L levels were significantly higher in squamous cancer compared with adenocarcinoma (0.75 versus 0.27 ng/ml; P < 0.05). Moreover, median sCD40L levels were higher in stage IV compared with nonmetastatic squamous lung cancer (1.02 versus 0.61 ng/ ml; P < 0.05). sCD40L levels significantly correlated with sP-selectin (P < 0.001), prothrombin fragment 1 ؉ 2 (P < 0.001), or thrombin-antithrombin III complex (P < 0.05) in squamous lung cancer, but only sP-selectin (P ‫؍‬ 0.011) was independently related to sCD40L.Conclusions: These findings indicate that elevated sCD40L levels can be preferentially found in patients with advanced squamous cancer and provide evidence that increased levels of this cytokine are associated to the occurrence of in vivo platelet activation.

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CD40 expression on human lung cancer correlates with metastatic spread

Abstract: These results suggest that CD40 expression on lung cancer may play a role in metastatic spread, and also may serve as a prognostic marker and an indicator of advanced disease.

Cited by 52 publications

References 16 publications

Expression of CD154 on renal cell carcinomas and effect on cell proliferation, motility and platelet‐activating factor synthesis

Expression of CD154 on renal cell carcinomas and effect on cell proliferation, motility and platelet‐activating factor synthesis

Expression of the co-signaling molecules CD40-CD40L and their growth inhibitory effect on pancreatic cancer in vitro

Soluble CD40 Ligand Plasma Levels in Lung Cancer

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