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The lymphatic system is largely considered to be the primary route for early dissemination of breast cancer, and the histopathological identification of tumor deposits in the axillary lymph node is one of the most powerful prognostic indicators for this disease. Until recently, the standard treatment for patients with operable breast cancer included the dissection of multiple axillary lymph nodes. However, in many cases, the removed lymph nodes are found to be free of metastases, indicating that some patients may have been subjected unnecessarily to the risks and morbidity associated with this procedure. A less invasive method for the assessment of lymph node status involves biopsy of the sentinel lymph node, a practice that is increasingly being used in the surgical setting. As the node that primarily drains the tumor and is most likely to harbor metastatic disease, the sentinel node is highly predictive of the histopathology of the remaining lymphatic basin and has been shown to accurately predict axillary lymph node status in up to 98% of cases. Tumor deposits ( 2 mm) present in lymph nodes are a sign that the tumor has spread beyond the confines of the breast, and this knowledge has important (but not fully understood) clinical implications in making treatmen decisions.Furthermore, the molecular mechanisms by which lymph node metastasis occurs require further elucidation. The identification of factors that functionally contribute to this process therefore has the potential to both provide a greater understanding of the biology of lymphatic metastasis in breast cancer, as well as to contribute to improved clinical management of the disease.
We hypothesize that one such factor may be the integrin-binding protein osteopontin (OPN). Clinical studies have demonstrated that OPN is overexpressed by many human cancers. In particular, we and others have found that OPN levels are elevated in the blood and primary tumors of patients with breast cancer, and in some cases this has been correlated with poor prognosis. The OPN protein backbone contains several highly conserved structural elements, including heparin- and calcium-binding domains, a thrombin-cleavage site, and an RGD (Arg-Gly-Asp) integrin-binding domain. It is therefore not surprising that OPN can interact with a diverse range of factors, including cell-surface receptors (integrins and CD44), secreted proteases (matrix metalloproteinases and urokinase-type plasminogen activator), and growth factor/receptor pathways (transforming growth factor /epidermal growth factor receptor, hepatocyte growth factor/Met, and vascular endothelial growth factor (VEGF)). These complex signaling interactions can result in changes in gene expression, which ultimately lead to alterations in cell properties involved in malignancy such as adhesion, migration, invasion, survival, angiogenesis, and metastasis.However, a direct functional link between OPN and lymphatic metastasis has not previously been demonstrated.
Recently, we have described a novel human breast cancer cell line (468LN) that preferentially metastasizes to the lymphatics in a rapid and aggressive manner. Interestingly, preliminary molecular characterization indicated that OPN was one of the most highly up-regulated genes in the 468LN cell line relative to the weakly metastatic MDA-MB-468 parental cell line, suggesting that OPN may play a role in lymphatic metastasis.We have also previously shown that OPN-induced changes in breast cancer cell behavior in vitro can occur by integrin-dependent mechanisms and that these OPN/integrin interactions occur via a conserved RGD sequence in the OPN protein backbone.We were therefore interested in determining whether OPN could functionally contribute to lymphatic metastasis and also whether the RGD integrin-binding region was important for this process. In the current study, we investigated the significance of OPN in lymphatic metastasis of breast cancer using both clinical and experimental approaches.
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Breast cancer is a leading cause of morbidity and mortality in women, mainly due to the propensity of primary breast tumors to metastasize to regional and distant sites such as lymph node, lung, liver, brain, and bone. Cancer cells may leave the primary tumor by one of two routes: either through hematogenous dissemination via blood circulation or by dissemination via the lymphatic system. Over the past decade or so, numerous studies have demonstrated that hematogenous metastasis is a complex process involving the escape of cancer cells from the primary tumor into the bloodstream (intravasation), survival in the circulation, arrest and extravasation into the secondary site, and initiation and maintenance of growth to form clinically detectable metastases. However, despite advances in our understanding of hematogenous metastasis, the process and mechanisms of lymphatic metastasis remain relatively understudied and poorly understood.
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作者:admin@医学,生命科学 2011-03-28 17:11
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