Abstract : Lung cancer is the leading cause of cancer mortality especially in developed countries. Despite multimodal therapy, prognosis is still dismal with an overall 5 year survival of 15%. Thus, efforts toward finding new potential therapeutic targets are important research directions.
Tumoral development implies interaction between the tumor cell and its environment which contributes actively to tumor development. Tumor environment (or tumor stroma) comprises the extracellular matrix, stromal cells, tumor endothelium and immune cells.
Endocan is a molecule present in this tumoral environment. Recently, it has been shown that endocan, a lung- and kidney-selective endothelial cell specific dermatan sulfate proteoglycan, binds through its glycan moiety to HGF/SF. In vitro, binding to endocan amplifies the growth factor mitogenic effect on cells of epithelial origin. Endocan also interacts by his protein with the LFA-1 integrin and modulate LFA-1/ICAM-1 interactions. Endocan is thus putatively involved in regulation of leucocytes transmigration from blood to tissues by blocking LFA-1/ICAM-1 interactions. This process is an essential step in firm adhesion of leukocytes to the endothelium and an important cofactor involved in cytotoxic leukocyte function. It has also been shown that endocan is expressed during an in vitro model of angiogenesis. Endocan is also overexpressed in various tumors as lung, breast, colon or kidney cancers.
We show that, in vivo, endocan overexpression by non-tumorigenic epithelial cells induces tumor formation, while overexpression by tumorigenic cells sharply increases the growth rate of resulting tumors. However endocan alone does not influence proliferation of tumor or endothelial cells. Thus endocan tumor-promoting capabilities result from amplification of growth factor effects on tumor cells.
While the tumorigenic effect requires the presence of the glycan chain, it also depends on the protein structure, as specific protein mutation results in loss of the tumor growth promotion effect. We show that the human endocan gene is transcribed into two alternatively-spliced variants which either retain (i.e. endocan) or exclude (i.e. endocan2) exon 2. This alternative spliced variant endocan2 does not participate at the endocan growth promotion effect.
We also showed that; in a model of subcutaneous tumors in SCID mice; anti-endocan antibodies slow tumor growth and this effect is associated with intra-tumoral accumulation of leukocytes.
In vitro, we show that VEGF represents a powerful inducer of endocan secretion by endothelial cells and that anti-VEGF antibodies abrogates VEGF induced endocan secretion.
We also shown that, in non small cell lung cancer, endocan is overexpressed and this concerns mainly the tumorigenic, exon 2 containing endocan isoform. Endocan expression is correlated with VEGF expression. Moreover, serum endocan values are correlated with patient survival, with a shorter survival in patients with high circulating levels of endocan. Interestingly serum endocan levels were correlated with presence of metastasis and nodal involvement but not with the primary tumor size.
We also investigated endocan levels in sepsis patients, were endothelial stimulation is an important pathological phenomenon. Serum endocan levels were elevated in patients with sepsis and they were correlated with another endothelial activation marker namely the von Willebradt factor. In this series high endocan levels were associated with increased sepsis severity and higher mortality.
We also show that serum endocan levels are elevated in patients with adenocarcinoma metastatic to the pleura. Endocan had also a prognostic value in this setting. Interestingly endocan levels were low, and had no prognostic significance in patients with malignant pleural mesothelioma.
We also investigated two putative diagnostic/prognostic markers of malignant pleural mesothelioma namely Soluble Mesothelin Related Peptides (SMRP) and osteopontin. SMRP are derived from membrane bound mesothelin (a molecule normally expressed by mesothelial cells) by either proteolitic cleavage or secretion of a mutated form. We show that SMRP is a good diagnostic marker for malignant pleural mesothelioma and offers a better diagnostic accuracy than osteopontin. However, both markers are independent prognostic factors in malignant pleural mesothelioma.
In conclusion we show that endocan play an important role in tumoral development by amplifying growth factor effects on tumoral cells and by inhibiting immune cell recruitment into the tumor. Serum endocan levels reflect the tumoral angiogenic stimulation and represent a prognostic factor in non small cell lung cancers. Endocan is also expressed by the endothelium in sepsis and has also a prognostic significance. We also evaluated two new markers in patients with malignant pleural mesothelioma and showed that both could have a diagnostic and prognostic utility.
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Contributor : Bogdan-Dragos Grigoriu <>
Submitted on : Saturday, July 25, 2009 - 8:56:04 AM
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  • HAL Id : tel-00407521, version 1



Bogdan Grigoriu. ROLE D'ENDOCAN DANS LA CROISSANCE TUMORALE ET EFFETS DES ANTICORPS ANTI-ENDOCAN SUR LE DEVELOPPEMENT TUMORAL. Biologie cellulaire. Université du Droit et de la Santé - Lille II, 2006. Français. ⟨tel-00407521⟩



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