The prognostic influence of lymphatic endothelium–specific hyaluronan receptor 1 in cancer: A systematic review

Lymphangiogenesis is a key process in cancer development and metastasis. Lymphatic vessel endothelial hyaluronan receptor 1 (LYVE‐1) is a widely used marker for lymphatic endothelial cells (LEC), which also mediates immune and cancer cell migration. Recently, LYVE‐1–positive tumor cells were shown to acquire LEC‐like phenotype and exploit this receptor for lymphatic dissemination. Furthermore, selective targeting of LYVE‐1 impaired the growth of cancer‐related vasculature and reduced metastasis in vivo, signifying its role in therapeutic and prognostic applications. Although numerous studies have investigated the role of LYVE‐1 in cancer, a unifying detailed review of its prognostic utility is lacking to date. Thus, we compiled and critically appraised evidence from clinical studies comprising a total of 2352 patients diagnosed with different types of cancer and using a variety of experimental approaches. Collectively, most studies revealed a significant association between LYVE‐1 overexpression and dismal outcome of at least one survival estimate. Furthermore, the importance of vasculature location, intra‐ or peritumoral, and the influence of various lymphangiogenesis‐related parameters, such as lymphatic vessel density and invasion, were discussed. However, the specificity of LYVE‐1 staining is challenged by its expression in non‐LEC cells, implying the need for double labelling to better estimate its prognostic significance. In conclusion, this is to our knowledge the first comprehensive systematic review on the prognostic value of LYVE‐1 in cancer. More well‐designed studies across different populations and the development of standardized protocols would be paramount for the consistency of LYVE‐1 findings and for its potential transferability to clinical practice in future.