Management of "unfavourable" carcinoma of unknown primary site: synthesis of recent literature.

Carcinomas of unknown primary (CUP) approximately represent 2-3% of all adult cancers. Various clinicopathological subsets of CUP have been identified, which may be treated with tailored approaches. Nevertheless, 80% of CUP do not fall into these subsets. Even when at least 4 prognostic models have been developed and validated in independent patient cohorts, there is no consensus or reliable guidance for estimating the prognosis of these "unfavourable" CUP. Consequently, targeting patients who benefit from palliative chemotherapy is difficult. Thirty-eight phase II trials were published between 1997 and 2011; a systematic analysis of these trials did not allow the recommendation of any of the tested regimens as a standard of care. Currently, there is only one published phase III clinical trial (Paclitaxel/carboplatin/etoposide versus gemcitabine/irinotecan); without significant difference between both regimens. Thus, with the promise of molecular profiling, we are waiting for a large collaborative clinical trial that validates the concept of targeted treatment in this population of patients with "unfavourable" CUP.

Egfl7 promotes tumor escape from immunity by repressing endothelial cell activation.

Downregulating the leukocyte adhesion molecules expressed by endothelial cells that line tumor blood vessels can limit the entry of immune effector cells into the tumor mass, thereby contributing to tumoral immune escape. Egfl7 (also known as VE-statin) is a secreted protein specifically expressed by endothelial cells in normal tissues and by cancer cells in various human tumors. High levels of Egfl7 correlate with higher tumor grade and poorer prognosis. Here we show that expression of Egfl7 in breast and lung carcinoma cells accelerates tumor growth and metastasis in immunocompetent mice but not in immunodeficient mice. Tumors expressing Egfl7 were infiltrated relatively poorly by immune cells and were characterized by reduced levels of immunostimulatory cytokines [IFN-γ, interleukin-12 (IL-12)] and fewer endothelial adhesion molecules [intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1)]. In vitro studies revealed that Egfl7 inhibited the expression of leukocyte adhesion molecules by endothelial cells, preventing lymphocyte adhesion. In contrast, Egfl7 did not exert any effects on immune cell activation. Human breast cancer lesions expressing high levels of Egfl7 also expressed less ICAM-1 and VCAM-1 in their blood vessels, also indicating an inverse correlation between expression levels of Egfl7 and IFN-γ. Thus, Egfl7 expression in tumors promotes tumor progression by reducing the expression of endothelial molecules that mediate immune cell infiltration. Our findings highlight a novel mechanism through which tumors escape immune control.