Knowledge about lymphangiogenesis has been lagging behind that about blood vessel angiogenesis. However, with the identification of lymphatic endothelial cell-specific proteins, such as the homeobox transcription factor Prox1 and the plasma membrane proteins podoplanin (a mucin-type glycoprotein), LYVE-1 (a hyaluronan receptor of the CD44 family), and VEGFR-3 (a receptor for VEGF-C and VEGF-D), it has become possible to study the mechanisms of lymphangiogenesis in vivo.1  Prox1 is required for lymphatic development, and VEGF-C/VEGFR-3 is essential for sprouting and proliferation of lymphatic endothelial cells in embryonic development. Studies of lymphangiogenesis in health and disease have attracted attention in recent years, not least because formation of new lymphatics early in the development of malignant tumors is of prime importance for metastasis of many types of human cancer. We know that tumors can induce formation of lymphatic vessels, but the trigger of lymphangiogenesis has not yet been identified.

CEACAM1, a member of the immunoglobulin superfamily, is a homophilic, transmembrane cell adhesion molecule that is abundantly expressed in epithelia, vessel endothelia, and hematopoietic cells.2  Like many other immunoglobulin superfamily molecules, CEACAM1 occurs as several differentially spliced isoforms, most of which differ only in their cytoplasmic domains. CEACAM1-L has a larger cytoplasmic domain with 2 phosphorylatable tyrosines; CEACAM1-S has a shorter cytoplasmic domain lacking tyrosines. Both isoforms participate in cell signaling and operate as signal regulating molecules. The signaling by CEACAM1-L is dependent on phosphorylation of the 2 tyrosines in its cytoplasmic domain, which can lead to recruitment of both Src-family tyrosine kinases and the protein tyrosine phosphatases SHP-1 and SHP-2, thereby influencing downstream signaling pathways.

Kilic and colleagues now provide the first evidence that CEACAM1 might function as a tumor-initiated lymphangiogenic switch. They show that CEACAM1 is expressed in lymphatic vessels of testicular, prostate, and bladder tumors, but not in normal tissues. The CEACAM1 expression appears much earlier in the lymphatic vessels than in tumor-associated blood microvessels, and before tumor invasion of the surrounding tissues. To investigate whether CEACAM1 might have a causative role in the formation of lymph vessels, Kilic et al used human dermal microvascular endothelial cells to demonstrate that CEACAM1-L does regulate the expression and activity of Prox1, which in turn causes expression of VEGFR-3 (see figure). CEACAM1-L also induced expression of VEGF-C, VEGF-D, podoplanin, and LYVE-1. These effects were dependent on the 2 tyrosine residues in the CEACAM1-L cytoplasmic domain. Thus, expression of CEACAM1-L initiates a positive feedback loop that leads to reprogramming of the microvascular endothelial cells to lymphatic endothelial cells. However, we do not yet know what agents cause up-regulation of CEACAM1 in the endothelial precursor cells. Kilic et al hypothesize that tumor-secreted members of the VEGF family may play a role. Other plausible candidates include cytokines released from lymphocytes or macrophages that are recruited to the tumor, since both TNF-α and interferon-γ have been shown to induce CEACAM1 expression in other cellular systems.

Primary malignant tumors produce as-yet unidentified factors that induce microvascular endothelial cells to express CEACAM1. Upon tyrosine phosphorylation of the cytoplasmic domain of CEACAM1-L, intracellular signals that up-regulate the expression of Prox1 are produced, leading in turn to production and surface expression of VEGFR-3. Expression of CEACAM1-L also induces expression of VEGF-C, VEGF-D, podoplanin, and LYVE-1, turning the cells into lymphatic endothelial cells. VEGF-C and VEGF-D activate VEGFR-3 in an autocrine loop, stimulating the reprogrammed cells to grow into lymph vessels.

Primary malignant tumors produce as-yet unidentified factors that induce microvascular endothelial cells to express CEACAM1. Upon tyrosine phosphorylation of the cytoplasmic domain of CEACAM1-L, intracellular signals that up-regulate the expression of Prox1 are produced, leading in turn to production and surface expression of VEGFR-3. Expression of CEACAM1-L also induces expression of VEGF-C, VEGF-D, podoplanin, and LYVE-1, turning the cells into lymphatic endothelial cells. VEGF-C and VEGF-D activate VEGFR-3 in an autocrine loop, stimulating the reprogrammed cells to grow into lymph vessels.

Do the new findings have any clinical significance? It is tempting to speculate that interfering with CEACAM1 expression and/or CEACAM1 signaling activities could inhibit formation of new lymph vessels, thereby diminishing tumor metastasis. However, before such a goal can be reached, we must learn more about CEACAM1's basic biology, which is very complex. Among other things, CEACAM1 inhibits tumor growth and epithelial cell proliferation, induces apoptosis of epithelial cells, delays apoptosis of granulocytes and monocytes, inhibits activation and proliferation of T lymphocytes, stimulates proliferation of B lymphocytes, inhibits the cytotoxic effects of T cells and NK cells, inhibits the activity of tumor-infiltrating lymphocytes, stimulates invasion of tumor cells and motility of endothelial cells, promotes blood vessel angiogenesis, and modulates vascular remodeling.2,4  In order to specifically interfere with only one of CEACAM1's function, such as triggering lymphangiogenesis, we must gain a much deeper knowledge of the molecular mechanisms for CEACAM1 signaling, both how it transmits information over the plasma membrane and how it affects downstream signaling, including how it influences the expression and activities of transcription factors such as Prox1.

Conflict-of-interest disclosure: The author declares no competing financial interests. ■

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