Lymphatic markers lymphangiogenesis and spread of clinical breast cancer

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Early metastasis to lymph nodes is a frequent complication in human breast cancer. However, the extent to which this depends on lymphangio-genesis or on invasion of existing lymph vessels remains ill-defined. It has been suggested that breast carcinomas invade and destroy lymph vessels rather than promoting their proliferation and nodal metastasis can proceed via pre-existing lymphatics (151). In another study, it was postulated that lymphangiogenesis does not appear to be a feature of invasive breast carcinomas (151). However, the same study revealed that a proportion of the peritumoral lymphatics contained tumour emboli associated with hyaluronan, indicating a possible role for LYVE-1/ hyaluronan interactions in lymphatic invasion or metastasis (151). Intra-tumoral lymphatic vessels have been demonstrated immunohistochemi-cally in breast cancer (152). Using a quantitative approach, the level of expression of a range of lymphangiogenic markers was analysed in a cohort of human breast cancer and compared with the clinical parameters and outcome demonstrated that a high transcript level of LYVE-1 in breast tissues compared with matched normal tissues (124). LYVE-1 level of expression was found to be higher in tumours that had spread to the regional lymph nodes (153). The increased lymphangiogenic markers were also seen together with an increase in the transcript levels of lymphangiogenic factor, VEGF-C and VEGF-D, in the same mammary tumours (154). While it is possible that this increase in lymphangiogenic markers in tumour tissues reflect merely as the presence of pre-existing lymphatic vessels by invading tumour cells (140, 141, 143, 144), the possibility may also strongly exists that the quantitation approach also sensitively detected minutes lymphatics with the tumour that cannot be seen by routine immunohistochemistry.

It has been recently reported that interleukin-7 is a lymphangiogenic factor both in vitro and in vivo (125, 126). It was also demonstrated that interleukin-7 and its receptor are aberrantly expressed in human breast cancer (123). The signalling complex molecules of IL-7R, including PI3-K, Jak-3, and Stat-5 are also aberrant in tumour tissues. Aggressive tumours particularly node positive tumours are seen with some most obvious changes.

Increased lymphangiogenesis was correlated to VEGF-C over-expression in metastatic breast cancer (34). This was associated with profound lung metastasis and enlargement of the peritumoral lymphatics (34, 155). The rate of lung metastases was directly correlated with the extent of lymphatic microvascular density inside the tumour mass (34). A recent study found that VEGF-C expression was only detectable in node positive breast cancers, whereas expression of VEGF-A detected in both node positive and node negative tumours (79). However, other studies claim that although VEGF-C is present, it is not always sufficient to induce the formation of functional lymphatic vessels (144). It has been recently demonstrated that HRG-beta 1 stimulated up-regulation of VEGF-C mRNA and protein of human breast cancer cells in a dosage- and time-dependent manner and that this upregulation was de novo RNA synthesis-dependent (156). The HRG-beta 1-induced increase in VEGF-C expression was effectively reduced by treatment with Herceptin, an antibody specifically against HER2 (156).

As tumours need neovascularization to grow and metastasise, microvascular density has been used as a measure of tumour angiogenesis which is correlated to prognosis (157-162). However, lymphatic microvessel density (LMVD) was rarely assessed because of the lack of a reliable lymphatic marker that is suitable for paraffin sections. Recently, antibodies against VEGFR-3 (80, 163) and LYVE-1 (164) that work on paraffin embedded tissue sections were used to evaluate the presence of intratumoral lymphatics and LMVD as a prognostic factor in several neoplasms. So far, most studies on LMVD have used VEGFR-3 as a lymphatic marker (8, 80, 163, 165). Although VEGFR-3 is a highly specific marker for normal adult lymphatic vessels, its upregulation in some tumour angiogenesis has made the role of LMVD as a prognostic factor unclear. Therefore, there is currently little conclusive evidence as to the influence of LMVD on patients' survival. In ovarian cancer for example, the LMVD has no influence on the progression of the disease and in cervical cancer an increased amount of LMVD may even be associated with a better prognosis (166, 167). It has been recently shown that increased flt-4-positive vessel density was correlated with lymph node metastasis and VEGF-D expression (168). High flt-4-positive vessel density may be a significant unfavourable prognostic factor for long-term survival in breast cancer (168).

The current targeting technologies make it possible to develop drugs into a targeted compound, thereby increasing the potency of the drug at the intended target tissue while reducing side effects elsewhere in the body (169-171). Inhibition of angiogenesis for example, is already considered a promising area in cancer therapy.

As stated above, tumours with a higher incidence of lymph node positivity express high levels of VEGF-C and VEGF-D, inhibition of VEGFR-3 signalling might be an attractive approach to inhibit cancer lymphatic metastasis. In transgenic mice with targeted expression of a soluble form of VEGFR-3 in the skin, lymphatic vessels initially formed normally, but the onset of the transgene expression led to regression of lymphatic vessels in embryos (172). Furthermore, a soluble VEGFR-3 protein produced via an adenovirus vector could inhibit lymphangiogenesis in a transplantable human breast carcinoma model using MCF-7 cell line in SCID mice (171). In another study, microhaemorrahge and the subsequent collapse of large tumour vessels was also reported in mice injected with blocking monoclonal antibodies against VEGFR-3 (60). Primary lymphoedema, a rare autosomal dominant disorder of the lymphatic system, was recently linked to mutations in the VEGFR-3 tyrosine kinase domain (173). Interruption of VEGFR-3 signalling results in lymphatic hypoplasia, underlining the importance of VEGFR-3 in the maintenance of lymphatic function during embryonic development (155, 173). Neutralising antibodies against VEGF-C and VEGF-D might also be an area of interest. It was recently revealed that the use of neutralizing antibodies against VEGF-D decreases the number of lymphatic metastases of the VEGF-D-293 tumours in the mammary fat pads of SCID/NOD mice (150). Therefore, the association of lymphangiogeneic factors with increased lymphatic growth and metastasis of cancers (34, 35, 148, 150) has made them an attractive target for an additional therapeutic modality against cancer.

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