Renewed Perspective on the Physiopathology of the Lymphatic System

Regulation of Interstitial Pressure

Lymph is essentially protein-rich interstitial fluid, which in turn is an ultrafiltrate of plasma. Unique to lymphatic capillaries are overlapping intercellular junctions that are formed by the extensive superimposition of adjacent LECs. LECs also have anchoring filaments, which link the basolat-eral plasma membrane to the adjacent extracellular matrix. As interstitial pressure rises, collagen fibers and other matrix components are forced apart. This in turn pulls on anchoring filaments, the result of which is an opening up of interen-dothelial junctions. Microarray analysis has revealed significant differences between BECs and LECs with respect to the expression of molecules that are involved in intra- and transcellular transport. Particularly highly represented in LECs were genes encoding proteins that control specificity of vesicle targeting and fusion. It is likely that LECs will display selectivity (quantitative and qualitative) with regard to regulating the formation of lymph.

Lymphedema is the term used to describe pathological conditions in which there is excessive, regional interstitial accumulation of protein-rich fluid. It can be either primary or secondary (i.e., acquired). Genetic studies have identified mutations in at least three genes that are associated with primary lymphedema: VEGFR-3, SOX18, and FOXC2. Inactivating mutations in the catalytic domain of VEGFR-3, a receptor tyrosine kinase for the lymphangiogenic factors VEGF-C and -D, are associated with Milroy's disease, an autosomal dominant form of early-onset lymphedema. SOX 18 is a transcription factor that has been implicated in dominant and recessive forms of hypotrichosis-lymphedema-telangiectasia. Late-onset primary lym-

phedema has been attributed to truncating mutations in the forkhead transcription factor FOXC2. Secondary lymphedema occurs as a result of disruption or obstruction of preexisting lymphatics following surgery, radiotherapy, trauma, and neoplastic or inflammatory conditions.

Regulation of Immune Function

The lymphatic system plays an important role in inflammatory and immunological responses. With regard to dendritic cells, following antigen capture, these cells migrate into lymph nodes via afferent vessels. Within the lymph nodes they present major histocompatibility (MHC)-bound antigens to lymphocytes. It is very likely that chemokines produced by LECs are required for stimulating migration of mature dendritic cells (and possibly lymphocytes) from the tissue interstitium into lymphatic capillaries, although the nature of these chemokines remains to be fully elucidated. However, previous studies have shown that CCL21 is expressed by lymphatic endothelium in the small intestine and liver. Cultured LECs produce CCL21. CCL21 is a potent chemoattractant for dendritic cells in vitro and enhances the emigration of dendritic cells from skin to regional lymph nodes. This effect is likely to be mediated by CCR7 on mature or cytokine-activated dendritic cells.

Tumor Cell Dissemination

VEGF-C and -D, which bind to and activate VEGFR-2 and -3, have been shown to induce lymphangiogenesis in vivo. Of particular importance is the discovery of a tight correlation between levels of VEGF-C in primary human tumors, and the presence of regional lymph node metastases. Experimental studies have demonstrated a direct role for VEGF-C and -D in the induction of lymphangiogenesis and the formation of regional lymph node metastases. This has been demonstrated in mouse transgenic and tumor xenotransplantation models. Both lymphangiogenesis and the formation of lymph node metastases could be efficiently inhibited by antagonists of VEGF-C and -D. Similarly, overexpression of a soluble form of VEGFR-3 in the skin of transgenic mice selectively inhibited spontaneous lymphan-giogenesis, which in turn resulted in lymphedema. However, one of the most important questions concerning lymphatic metastases still remains to be answered: Do tumor cells employ existing lymphatics for their dissemination, or does dissemination require the de novo formation of lymphatic capillaries (lymphangiogenesis)? With regard to human tumors, there is at present very little evidence for peri- or intratumoral lymphangiogenesis. This then begs the question: Why are high levels of VEGF-C in primary tumors associated with regional lymph node metastases?

Tumor cell dissemination via the lymphatic system requires the intravasation of tumor cells into lymphatic capillaries. Very little is known about how this process is regulated, but it is conceivable that LEC-derived chemokines may play a role. Apart from the fragmentary data on cultured LECs (see earlier discussion), very little is known about which chemokines are produced by LECs in vivo. However, evidence is accumulating that tumor cells express chemokine receptors (CXCR4, CCR7, and CCR10) that mediate their dissemination to lymph nodes. Signaling via these receptors mediates intracellular calcium flux, actin polymerization, changes in integrin expression, formation of pseudopodia, and tumor cell chemotaxis. Neutralization of the CXCL12/CXCR4 interaction in vivo significantly reduces metastasis of breast cancer cells to regional lymph nodes and lung.

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Essentials of Human Physiology

Essentials of Human Physiology

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