Influence of L1-CAM expression of breast cancer cells on adhesion to endothelial cells.

PURPOSE: Expression of the adhesion molecule L1-CAM (L1) has been shown to correlate with early recurrence in breast cancer. Here, we investigated whether L1-CAM expression of breast cancer cells might influence adherence to human pulmonary microvascular endothelial cells (HPMEC) and thus promote metastasis. METHODS: MDA-MB231-Fra2 breast cancer cells that express high levels of L1-CAM (L1(high) cells) were stably transfected to generate clones with strong L1-CAM downregulation. Adhesion to activated HPMEC was studied in dynamic cell flow and static assays. Potential binding partners on endothelial cells were identified by blocking experiments and adhesion assays after coating of the flow channels with recombinant proteins. RESULTS: Adhesion of L1(high) cells to activated HPMEC was significantly higher compared to L1l(ow) clones under flow conditions. Blocking experiments and adhesion assays with recombinant proteins identified activated leucocyte cell adhesion molecule (ALCAM) or L1 itself, but not ICAM-1, as potential binding partners on endothelial cells. E-selectin blocking antibodies strongly diminished the adherence of breast cancer cells irrespective of their L1-CAM expression. CONCLUSIONS: Our experiments indicate that L1-CAM expression on breast cancer cells can promote adherence to activated endothelial cells by binding to endothelial L1-CAM or ALCAM. This mechanism might lead to increased metastasis and a poor prognosis in L1-CAM-positive carcinomas in vivo. Therefore, L1-CAM might be a suitable therapeutic target in breast cancers with a high L1-CAM expression.

Adhesion of small cell lung cancer cells to E- and P-selectin under physiological flow conditions: implications for metastasis formation.

Haematogenous metastasis of small cell lung cancer (SCLC) is still a poorly understood process and represents the life threatening event in this malignancy. In particular, the rate-limiting step within the metastatic cascade is not yet clearly defined although, many findings indicate, that extravasation of circulating tumour cells is crucially important as most tumour cells within the circulation undergo apoptosis. If extravasation of SCLC tumour cells mimics leukocyte-endothelial interactions, SCLC cells should adhere to E- and P-selectins expressed on the luminal surface of activated endothelium. The adhesion to E- and P-selectin under physiological shear stress with regard to adhesive events, rolling behaviour and rolling velocity was determined in the human SCLC cell lines SW2, H69, H82, OH1 and OH3. OH1 SCLC cells adhered best to recombinant human (rh) E-selectin FC-chimeras and human lung endothelial cells (HPMEC), H82 SCLC cells adhered best to activated human umbilical vein endothelial cells (HUVEC) under physiological shear stress. As OH1 cells had also produced by far the highest number of spontaneous lung metastases when xenografted into pfp/rag2 mice in previous experiments our findings implicate that adhesion of SCLC cells to E-selectin is of paramount importance in SCLC metastasis formation.