| BACKGROUNDBreast cancer is the most common carcinoma in Chinese women. The metastasis of breast cancer cells usually occurs lymphatic channels. Axillary lymph node is the most important site of breast cancer lymphatic metastasis and its metastatic degree is closely related to patient's prognosis. For several years the role of routine total axillary dissection has been questioned due to the relatively low incidence of axillary lymph node metastasis in patients with small tumors, potential morbidity, cost, and lack of significant therapeutic value. In China, however, axillary lymph node dissection remains a mainstay of surgical treatment. But the optimal level of axillary lymph node dissection, such as total axillary dissection, partial axillary dissection or sentinel lymph node biopsy is still controversial.Most experimental work addressing systemic tumor dissemination has focused on hematogenic spread. Little is known about the mechanism by which tumor cells enter, interact with, and are transported within lymphatic vessels. Study of the lymphatic system has recently been promoted by the identification of molecules that act as markers of the lymphatic endothelium. One of these molecules is a fms-like tyrosine kinase receptor called VEGFR-3 (or Flt-4). VEGFR-3 is activated in response to its ligand, VEGF-C, causing stimulation of lymphangiogenesis, the new growth of lymphatic vessels. Recently, LYVE-1 was identified as the first hyaluronan recepter present on lymph vessels but completely absent from blood vessels. Clinicalfindings have long suggested that by providing a pathway for tumor cell dissemination, tumor-associated lymphatics are a key component of metastatic spread. It is not known whether increased expression of VEGF-C, VEGFR-3 and LYVE-1 in "tumor region", "nearer-tumor region"and"farther-tumor region" of human breast with carcinoma is correlate with lymphangiogenesis and dissemination of tumor cells to regional lymph nodes.SECTION 1 Clinical and pathological study of axillary lymphnodes metastasis in breast cancerObjective To study the relationship of the size, location and age with axillary lymphnodes metastasis in breast cancer. To explore the optimal level of axillary lymph nodedissection.Methods The relation between the size, location and age and axillary lymph nodesmetastasis were studied in 126 patients with breast cancer.Results In the 126 breast cancer patients, axillary lymph nodes metastasis werefound in 65 patients, the overall metastasis rate was 51.59%. Axillary lymph nodesmetastasis rate was 50% in level â… , 26.98% in level â…¡, 16.67% in level â…¢,respectively. There were no difference in axillary lymph node metastasis rate amongcarcinomas which located in outer, middle and inner part of the breast. There was astatistically positive correlation between tumor size and axillary lymph nodemetastasis rate. The level â…¢ axillary lymph node metastasis rate of T1 breast cancerwas lowest, but still was 6.38%. There were also no difference between patients whowere elder and not elder than 40.Conclusions1. The metastasis rates were difference among level â… level â…¡ and levelâ…¢ axillary lymph nodes, level I was higher than level â…¡ ,and level â…¡ was higher than levelâ…¢.2. There were same incidence of axillary lymph node metastasis rate among carcinomas which located in outer, middle and inner part of the breast.3. There was a statistically positive correlation between tumor size and axillarylymph node metastasis rate. The larger of the tumor,the higher of the rate of axillary lymph node metastasis.4. The level â…¢ axillary lymph node metastasis rate of T1 breast cancer was lowest, but still was 6.38%. We might not give up level â…¢ axillary lymph node dissection randomly.5. Axillary lymph node dissection might not be given up randomly in old breast cancer patients.SECTION 2 Relationship between expression of VEGFC andVEGFR-3 and axillary lyniphnode metastasisObjective To study the relationship between lymphangiogenesis and axillary lymph nodes metastasis in breast cancer.Methods Immunohistochemical staining was used to detect the expression of VEGF-C,VEGFR-3 and LYVE-1 in "tumor-region", "nearer-tumor region" and "farther-tumor region" of 62 breast cancer patients. The relationship between the expression of VEGF-C,VEGFR-3 and LYVE-1 and axillary lymph nodes metastasis were studied in the 62 breast cancer patients.Results If the expression of VEGF-C in "tumor-region" was positive ,there were some levels of VEGF-C expression in "nearer-tumor region" and "farther-tumor region". If the expression of VEGF-C in "tumor-region" was negative ,there were also no VEGF-C expression in "nearer-tumor region" and "farther-tumor region" in the same patient. The expression rate of VEGF-C was highest in "tumor-region". From "tumor-region" to "nearer-tumor region"and to "farther-tumor region", the tendency of VEGF-C expression rate was decreased. The expression rate of VEGFR-3 and LYVE-1 in the three regions were rather lower than VEGF-C and no statistical difference among the three regions in the expression rate of VEGFR-3 and LYVE-1 was found. The relationship between VEGF-C expression in "tumor-region" ,"nearer-tumor region" and "farther-tumor region" and axillary lymph nodes metastasis was found. The relationship between VEGFR-3 expression andaxillary lymph nodes metastasis rate was just found in "nearer-tumor region". But no relation of LYVE-1 expression with axillary lymph nodes metastasis rate was found in the three regions. Conclusions1. The overexpression of VEGF-C reflect the biological characteristic and behavior of breast cancer.2. If overexpression of VEGF-C only in "tumor-region", it had no relation with axillary lymph nodes metastasis rate. When overexpression of VEGF-C was not only in "tumor-region" but also in "nearer-tumor region" and/or "farther-tumor region", it had relation with higher axillary lymph nodes metastasis rate. Therefore, "nearer-tumor region" and"farther-tumor region"might have important role in axillary lymph nodes metastasis of breast cancer.3. The expression rate of VEGFR-3 in the three regions was rather low. Just VEGFR-3 expression in "nearer-tumor region" had relation with axillary lymph nodes metastasis rate. So that, the"nearer-tumor region" might be very important in axillary lymph nodes metastasis.4. The overexpression of VEGF-C and its receptor VEGFR-3 in tumor and"nearer-tumor region" mighe be one of the mechanisms of axillary lymph nodes metastasis in breast cancer.5. The expression rate of LYVE-1 in the three regions were very low and there was no statistical difference among the three regions in the expression rate of LYVE-1. There was no relation of LYVE-1 expression in the three regions with axillary lymph nodes metastasis rate.SECTION 3 Relationship between expression of VEGF-C , VEGFR-3 and LYVE-1 mRNA and axillary lymphnode metastasis inbreast cancerObjective To investigate the potential ability of lymphangiogenesis and itsrelationship with axillary lymph nodes metastasis in breast cancer.Methods The expression of VEGF-C,VEGFR-3 and LYVE-1 was detected withRT-PCR method in"tumor-region","nearer-tumor region" and "farther-tumor region"of 62 breast cancer patients. The relationship between the expression ofVEGF-CVEGFR-3 and LYVE-1 mRNA and axillary lymph nodes metastasis werestudied in these patients.Results The expression rate of VEGF-CmRNA was highest in "tumor-region".From "tumor-region" to "nearer-tumor region"and to "farther-tumor region", thetendency of VEGF-CmRNA expression rate was decreased. The expression rate ofVEGFR-3mRNA and LYVE-1mRNA in the three regions were rather higher thanVEGF-CmRNA. No relationship between VEGF-CmRNA, VEGFR-3mRNA,LYVE-1mRNA expression in "tumor-region" and axillary lymph nodes metastasisrate was found.Conclusions1. Similar to immunohistochemical study, the tendency of VEGF-CmRNA expression rate from "tumor-region" to "nearer-tumor region"and to "farther-tumor region" was decreased. The overexpression of VEGF-C mRNA reflect the biological characteristic and behavior of breast cancer.2. The expression rate of VEGFR-3mRNA and LYVE-1mRNA in the three regions were rather high. It implied that the breast with cancer had widespread potential ability of lymphangiogenesis.3. There was no relationship between VEGF-CmRNA, VEGFR-3mRNA,LYVE-lmRNA expression in "tumor-region" and axillary lymph nodes metastasis rate. It proved that the expression of VEGF-CmRNA VEGFR-3mRNA and LYVE-1 mRNA just increased the potential ability of lymphangiogenesis, but they could not influnce the rate of axillary lymph node metastasis clinically.SECTION 4 Expression of VEGF-C , VEGFR-3 and LYVE-1mRNA in human breast cancer cell linesObjective To investigate the potential ability of lymphangiogenesis in different human breast carcinoma cell lines.Methods The expression of VEGF-C,VEGFR-3 and LYVE-1 was detected with RT-PCR method in MCF-7, MCF-7/Adr, MDA-MB-231,MDA-MB-435 human breast carcinoma cell lines.Results In the MCF-7 cell line, there was no expression of VEGF-CmRNA and LYVE-1 was detected and VEGFR-3mRNA expression was in low level. There was high level expression of VEGF-CmRNA and increased expression of VEGFR-3mRNA was detected in MCF-7/Adr cell line. In MDA-MB-231cell line, a high level expression of VEGF-CmRNA and middle level expression of VEGFR-3mRNA, but no expression of LYVE-1 mRNA was detected. In MDA-MB-435 cell line, a low level expression of VEGF-CmRNA and no expression of VEGFR-3mRNA, but middle level expression of LYVE-1 mRNA was detected. Conclusions1. Compare with MCF-7 which had no expression of VEGF-C mRNA, MCF-7/Adr cell line had high level expression of VEGF-C mRNA and increased expression of VEGFR-3mRNA. It implied that expression of VEGF-C mRNA and VEGF-C mRNA might have a important role of higher malignancy of MCF-7/Adr than MCF-7 cell line.2. The mechanism of MDA-MB-231 cell line metastasis might be related withexpression of VEGF-C and VEGFR-3. And the mechanism of MDA-MB-435 cell line metastasis might be related with expression of LYVE-1.
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