VEGF-C及Flt-4在非小细胞肺癌中的临床意义
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摘要
作为恶性肿瘤相关死亡的主要原因,肺癌是目前威胁人类健康的首要问题。一项统计报道,2006年,美国肺癌的发病人数为174,470。
非小细胞肺癌占肺癌总数的70%-80%,因此,对非小细胞肺癌的治疗将是医务工作者的一个挑战。大多癌症相关死亡的原因主要是肿瘤细胞的转移,而淋巴结是肿瘤最常见的转移部位。众所周知,区域性淋巴结转移是非小细胞肺癌最常见的转移方式,即使是在早期的非小细胞肺癌中也是如此。也就是说,‘N’的状况是肺癌分期和临床治疗的主要决定因素。
肿瘤细胞一旦出现前哨淋巴结的转移,它们将进一步向远处的淋巴结扩散。TNM系统通常是用来评价肿瘤进展、淋巴结转移及远处转移的主要模式,一些临床研究已证实,淋巴系统的侵犯是非小细胞肺癌的主要预后因素,因此,淋巴系统将成为非小细胞肺癌治疗和诊断的新的靶点。
血管生成是肿瘤生长和转移的必须条件已为被广泛接受,局部无血管生成,肿瘤生长至2mm3将不再生长。另外,血管生成与原发性肿瘤的转移有关已有报道,临床研究也已证实血管生成与人类肿瘤的转移有关,预后不良。近年来,一些研究表明,淋巴管生成也与肿瘤的转移有关,因此,对血管生成与淋巴管生成的了解和调控可能是肿瘤治疗的有效的策略。
然而,几十年来由于缺乏人类肿瘤的淋巴管可信的标记物和淋巴管生成因子,淋巴系统转移的机制仍不清楚,使得我们对淋巴系统知识的了解滞后于对血管系统的了解。
近来,由于分子生物学的进步,揭示了肿瘤淋巴系统转移的机制。血管内皮生长因子(VEGF)家族,其编码成员有VEGF-A, -B, -C, -D, and–E,及其受体家族,因为它们具有能够促进肿瘤的生长和转移的血管生成和淋巴管生成的特性,被认为是一组非常重要的生长因子和受体。
血管内皮生长因子-C通过与受体VEGFR-3 (也称为Flt-4)及VEGFR-2间的信号传导,具有血管生成和淋巴管生成的生长因子作用。
在血管内皮生长因子受体家族成员中,Flt-4,也就是VEGFR-3,是VEGF-C和VEGF-D的受体。在胚胎时期,Flt-4可以在所有胚胎内皮表达,而在成年以后,其表达明显受到限制,主要表达于淋巴管内皮细胞。近来的研究中已将其作为淋巴内皮细胞的标记物,也发现在多种人类肿瘤中表达。
实验研究表明肿瘤通过释放VEGF-C或VEGF-D而激活Flt-4诱导淋巴管形成,从而促使淋巴结的转移。抑制了Flt-4的信号传导可以抑制淋巴管的形成和淋巴结的转移。既然如此,Flt-4可以作为多种恶性肿瘤的诊断和治疗的靶点。然而,在非小细胞肺癌中,仅有少数临床研究与VEGF-C (或VEGF-D),和Flt-4有关报道,而且有关VEGF-C (或VEGF-D),和Flt-4在肿瘤细胞和/或内皮细胞表达的意义尚存争议,尤其是VEGF-C (或VEGF-D),和Flt-4在内皮细胞的表达与肿瘤预后的意义。因此,我们采用半定量PCR及Western blot方法,对VEGF-C以及VEGFR-3 mRNA及蛋白在非小细胞肺癌的表达进行评估,评价其与非小细胞肺癌病人的临床病理因素相互之间的关系,包括淋巴结转移的情况。
自2006年12月至2007年6月,相继有78例病理分期为I-IIIA期非小细胞肺癌病人在北京胸科医院接受了外科手术治疗,并对其组织标本234份应用半定量PCR及171份应用Western blot的方法进行了研究。术后病理分期根据1997年重新修订的TNM分期进行再分期,对其不同的病理类型、分期、分化程度及其他临床特性与VEGF-C和VEGFR-3mRNA及蛋白的表达进行分析。
1.半定量PCR测定结果:
VEGF-C mRNA在癌组织及癌旁组织的相对含量明显高于正常组织(VEGF-C mRNA 0.302±0.177, 0.209±0.131, 0.152±0.89, P<0.05),Flt-4在癌组织中的相对含量明显高于正常组织(0.278±0.182 vs 0.181±0.128,P<0.05),在癌旁中的相对含量也高于正常组织,但无统计学意义(0.199±0.128 vs 0.181±0.128, P> 0.05)。
VEGF-C和Flt-4 mRNA的表达与临床病理特性相互之间的关系显示,在淋巴结转移组及病理分期组,VEGF-C或Flt-4 mRNA的表达水平无论是在癌组织中,还是在癌旁组织中均有明显统计学意义,P<0.001。而在不同分化程度分组中,VEGF-C和Flt-4 mRNA的表达仅在癌旁组织中有统计学意义,与其他临床病理因素无明显相关性。
2.Western blot测定结果:
在78例非小细胞肺癌病人中,对57例病人共171例组织标本进行了癌组织、癌周及肺正常组织VEGF-C的蛋白水平测定,VEGF-C的蛋白表达水平在癌组织、癌周及正常组织中的表达量分别为0.631±0.300 ,0.502±0.246, 0.531±0.286,其中癌组织的VEGF-C的蛋白水平表达与正常组织中的表达有明显统计学意义,P=0.000,而癌组织与癌旁组织、癌旁组织与正常组织中VEGF-C的蛋白表达水平无统计学差异,P=0.201。与所有临床病理因素之间的相互关系,均无明显统计学意义。
本实验研究证实,VEGF-C mRNA在癌组织及癌旁组织的相对含量明显高于正常组织,而且VEGF-C及Flt-4 mRNA的表达与肿瘤的淋巴结转移及分期有关,针对VEGF-C/ Flt-4的靶向治疗可能对肿瘤是有意义的,因此对VEGF-C/ Flt-4有调节作用的因子的不断发现及其特性的不断了解,是限制肿瘤的扩散一种必要的新的方法,特别是发现能够阻断VEGF-C/ Flt-4信号传导的新药,可能为抗肿瘤治疗提供一种有用的方法。
As the number one overall cause of the cancer-related death, lung cancer, whose most common type is non-small cell lung cancer(NSCLC) , is the leading public health concern worldwide. Of the estimated 174,470 people in the United State who were diagnosed with lung cancer in 2006.
Non–small cell lung cancer (NSCLC) accounts for 70% to 80% of primary lung cancer. So treatment of NSCLC will be a challenge for medical stuff to deal with. The metastatic spread of tumor cells is responsible of the majority of cancer-related deaths. Lymph nodes are the most common sites of metastasis.
Non–small cell lung cancer (NSCLC) is well-known for its ability to involve regional lymph nodes even at the early stages of tumor growth. Therefore,‘N status’is a major determinant for the staging and clinical management of lung cancer.
Once tumor cells are established in the sentinel lymph node (SLN), they can further metastasize to distant lymph nodes and beyond. Tumor-node-metastasis (TNM) system, generally used in the evaluation of tumor progression, and nodal involvement as well as distant metastasis,is the critical factor to determine the prognosis of NSCLC. Several clinical studies have shown that lymphatic invasion is a significant prognostic factor in NSCLC. Thus, it should be a new target in the diagnosis and therapy of NSCLC.
It is widely accepted that angiogenesis is essential for both tumor growth and metastasis. In the absence of local angiogenesis, tumors cannot grow beyond 2 mm3 . In addition, tumor angiogenesis has been reported to be associated with metastasis of primary tumors. Clinical studies in human cancer patients have also demonstrated that angiogenesis is associated with tumor metastasis and a poor prognosis. Furthermore, current studies have indicated that lymphangiogenesis is also associated with tumor metastasis. Thus, understanding and controlling angiogenesis and lymphangiogenesis could lead to effective strategies for cancer treatment.
However, the mechanisms of lymphatic metastasis have remained unclear for decades, mainly due to the lack of reliable markers for lymphatic vessels and identified lymphangiogenic growth factors in human cancers, and it makes our knowledge of the lymphatic system of lung cancer lags far behind that of the vascular system.
Recent advances in molecular biology have revealed mechanism of lymphatic spread in malignant tumors. The vascular endothelial growth factor (VEGF) gene family, which encodes five polypeptide growth factors, VEGF-A, -B, -C, -D,and -E, and their receptor family are particularly important a group of growth factors and receptors because of their angiogenic and lymphangiogenic properties that promote the growth and metastasis of neoplasma.
Vascular endothelial growth factor-C has been characterised as a lymphangiogenic and angiogenic growth factor and has been shown to signal through the receptors VEGFR-3 (also called Flt-4) and VEGFR-2. Among the vascular endothelial growth factor receptor (VEGFR) family members, Flt (fms-like tyrosine kinase)-4 is a receptor for VEGF-C and VEGF-D. Flt-4 is expressed on all of the embryonic endothelia, but its expression is largely restricted to the lymphatic endothelium in adult tissues. Recent studies have indicated that VEGFR-3, which has been proposed as a marker for lymphatic endothelial cells, is also expressed in a variety of human malignancies.
Experimental studies have revealed that tumors can actively induce the formation of lymphatic vessels (lymphangiogenesis)– via release of VEGF-C or VEGF-D, which activating of Flt-4, and thereby promote metastasis to draining lymph nodes. Moreover, inhibition of Flt-4 signaling can suppress tumor lymphangiogenesis and lymph node metastasis. Thus, Flt-4 can also be an important diagnostic and therapeutic target for treating a variety of malignant tumors.
In NSCLC, however, only a few clinical studies on VEGF-C (or VEGF-D), and Flt-4 expression have been reported, and clinical significance of VEGF-C (or VEGF-D), and Flt-4 expression on tumor cells and/or on endothelial cells remains controversial. Particularly, no study has documented a prognostic value of VEGF-C (or VEGF-D), and Flt-4 expression in endothelial cells. Therefore, we assessed the expression of VEGF-C and VEGFR-3 mRNA and protein in NSCLC by RT-PCR and Western Blot to demonstrate how they correlated with clinicopathological factors, including lymph node metastasis.
A total of 78 consecutive patients with pathological stage I-IIIA NSCLC who underwent complete tumor resection without any preoperative therapy at Beijing Chest Hospital between December 2006 to June 2007, and whose 234 histologic specimens are available for PCR and 171 histologic specimens for Western blot were prospectively studied.
Pathological stage was reevaluated and determined with the present TNM classification as revised in 1997. For analyses according to the different pathological type, different stage and different differentiation of cancer cells as well as other clinical features.
PCR detection result:
The relative contents of VEGF-C mRNA in cancer tissue and in paracancer were higher than those in normal tissues(VEGF-C mRNA 0.302±0.177, 0.209±0.131, 0.152±0.89) P<0.05,and the relative content of Flt-4 mRNA in cancer tissue was higher than that in normal tissue,(0.278±0.182 vs 0.181±0.128,P<0.05); the content in paracancer tissue was also higher than that in normal tissue,(0.199±0.128 vs 0.181±0.128, P> 0.05).
The relationship between VEGF-C or Flt-4 mRNA expression and clinicopathological features are shown that the expression level of VEGF-C mRNA and Flt-4 both in cancer tissue and paracancer tissue have significantly different in lymph node groups and stage groups. In paracancer group, the expression level of VEGF-C mRNA and Flt-4 has significantly different in histological grade group. There were no significant different in different age, different tumor position, different tumor size and different pathological types.
Westem blot detection:
171 histologic specimens in 57 patients were detected by Westem blot among 78 NSCLC, the protein level of VEGF-C in cancer tissue, paracancer tissue and normal tissue were 0.631±0.300,0.502±0.246, 0.531±0.286, respectively, there was significant different between cancer tissue and normal tissue, P=0.000. but for all the clinicopathological features, there were no significant different between age, gender, pathological types, stages, lymph node status and differentiation.
In conclusion, the present study gives evidence that VEGF-C and Flt-4 might play an important role in lymph node metastasis in NSCLC, Targeting the VEGF-C/Flt-4 may be therapeutically significant for certain types of tumours. Thus, the continued discovery and characterization of factors that regulate VEGF-C or Flt-4 will be essential for developing new therapies that limit the spread of cancer.
非小细胞肺癌占肺癌总数的70%-80%,因此,对非小细胞肺癌的治疗将是医务工作者的一个挑战。大多癌症相关死亡的原因主要是肿瘤细胞的转移,而淋巴结是肿瘤最常见的转移部位。众所周知,区域性淋巴结转移是非小细胞肺癌最常见的转移方式,即使是在早期的非小细胞肺癌中也是如此。也就是说,‘N’的状况是肺癌分期和临床治疗的主要决定因素。
肿瘤细胞一旦出现前哨淋巴结的转移,它们将进一步向远处的淋巴结扩散。TNM系统通常是用来评价肿瘤进展、淋巴结转移及远处转移的主要模式,一些临床研究已证实,淋巴系统的侵犯是非小细胞肺癌的主要预后因素,因此,淋巴系统将成为非小细胞肺癌治疗和诊断的新的靶点。
血管生成是肿瘤生长和转移的必须条件已为被广泛接受,局部无血管生成,肿瘤生长至2mm3将不再生长。另外,血管生成与原发性肿瘤的转移有关已有报道,临床研究也已证实血管生成与人类肿瘤的转移有关,预后不良。近年来,一些研究表明,淋巴管生成也与肿瘤的转移有关,因此,对血管生成与淋巴管生成的了解和调控可能是肿瘤治疗的有效的策略。
然而,几十年来由于缺乏人类肿瘤的淋巴管可信的标记物和淋巴管生成因子,淋巴系统转移的机制仍不清楚,使得我们对淋巴系统知识的了解滞后于对血管系统的了解。
近来,由于分子生物学的进步,揭示了肿瘤淋巴系统转移的机制。血管内皮生长因子(VEGF)家族,其编码成员有VEGF-A, -B, -C, -D, and–E,及其受体家族,因为它们具有能够促进肿瘤的生长和转移的血管生成和淋巴管生成的特性,被认为是一组非常重要的生长因子和受体。
血管内皮生长因子-C通过与受体VEGFR-3 (也称为Flt-4)及VEGFR-2间的信号传导,具有血管生成和淋巴管生成的生长因子作用。
在血管内皮生长因子受体家族成员中,Flt-4,也就是VEGFR-3,是VEGF-C和VEGF-D的受体。在胚胎时期,Flt-4可以在所有胚胎内皮表达,而在成年以后,其表达明显受到限制,主要表达于淋巴管内皮细胞。近来的研究中已将其作为淋巴内皮细胞的标记物,也发现在多种人类肿瘤中表达。
实验研究表明肿瘤通过释放VEGF-C或VEGF-D而激活Flt-4诱导淋巴管形成,从而促使淋巴结的转移。抑制了Flt-4的信号传导可以抑制淋巴管的形成和淋巴结的转移。既然如此,Flt-4可以作为多种恶性肿瘤的诊断和治疗的靶点。然而,在非小细胞肺癌中,仅有少数临床研究与VEGF-C (或VEGF-D),和Flt-4有关报道,而且有关VEGF-C (或VEGF-D),和Flt-4在肿瘤细胞和/或内皮细胞表达的意义尚存争议,尤其是VEGF-C (或VEGF-D),和Flt-4在内皮细胞的表达与肿瘤预后的意义。因此,我们采用半定量PCR及Western blot方法,对VEGF-C以及VEGFR-3 mRNA及蛋白在非小细胞肺癌的表达进行评估,评价其与非小细胞肺癌病人的临床病理因素相互之间的关系,包括淋巴结转移的情况。
自2006年12月至2007年6月,相继有78例病理分期为I-IIIA期非小细胞肺癌病人在北京胸科医院接受了外科手术治疗,并对其组织标本234份应用半定量PCR及171份应用Western blot的方法进行了研究。术后病理分期根据1997年重新修订的TNM分期进行再分期,对其不同的病理类型、分期、分化程度及其他临床特性与VEGF-C和VEGFR-3mRNA及蛋白的表达进行分析。
1.半定量PCR测定结果:
VEGF-C mRNA在癌组织及癌旁组织的相对含量明显高于正常组织(VEGF-C mRNA 0.302±0.177, 0.209±0.131, 0.152±0.89, P<0.05),Flt-4在癌组织中的相对含量明显高于正常组织(0.278±0.182 vs 0.181±0.128,P<0.05),在癌旁中的相对含量也高于正常组织,但无统计学意义(0.199±0.128 vs 0.181±0.128, P> 0.05)。
VEGF-C和Flt-4 mRNA的表达与临床病理特性相互之间的关系显示,在淋巴结转移组及病理分期组,VEGF-C或Flt-4 mRNA的表达水平无论是在癌组织中,还是在癌旁组织中均有明显统计学意义,P<0.001。而在不同分化程度分组中,VEGF-C和Flt-4 mRNA的表达仅在癌旁组织中有统计学意义,与其他临床病理因素无明显相关性。
2.Western blot测定结果:
在78例非小细胞肺癌病人中,对57例病人共171例组织标本进行了癌组织、癌周及肺正常组织VEGF-C的蛋白水平测定,VEGF-C的蛋白表达水平在癌组织、癌周及正常组织中的表达量分别为0.631±0.300 ,0.502±0.246, 0.531±0.286,其中癌组织的VEGF-C的蛋白水平表达与正常组织中的表达有明显统计学意义,P=0.000,而癌组织与癌旁组织、癌旁组织与正常组织中VEGF-C的蛋白表达水平无统计学差异,P=0.201。与所有临床病理因素之间的相互关系,均无明显统计学意义。
本实验研究证实,VEGF-C mRNA在癌组织及癌旁组织的相对含量明显高于正常组织,而且VEGF-C及Flt-4 mRNA的表达与肿瘤的淋巴结转移及分期有关,针对VEGF-C/ Flt-4的靶向治疗可能对肿瘤是有意义的,因此对VEGF-C/ Flt-4有调节作用的因子的不断发现及其特性的不断了解,是限制肿瘤的扩散一种必要的新的方法,特别是发现能够阻断VEGF-C/ Flt-4信号传导的新药,可能为抗肿瘤治疗提供一种有用的方法。
As the number one overall cause of the cancer-related death, lung cancer, whose most common type is non-small cell lung cancer(NSCLC) , is the leading public health concern worldwide. Of the estimated 174,470 people in the United State who were diagnosed with lung cancer in 2006.
Non–small cell lung cancer (NSCLC) accounts for 70% to 80% of primary lung cancer. So treatment of NSCLC will be a challenge for medical stuff to deal with. The metastatic spread of tumor cells is responsible of the majority of cancer-related deaths. Lymph nodes are the most common sites of metastasis.
Non–small cell lung cancer (NSCLC) is well-known for its ability to involve regional lymph nodes even at the early stages of tumor growth. Therefore,‘N status’is a major determinant for the staging and clinical management of lung cancer.
Once tumor cells are established in the sentinel lymph node (SLN), they can further metastasize to distant lymph nodes and beyond. Tumor-node-metastasis (TNM) system, generally used in the evaluation of tumor progression, and nodal involvement as well as distant metastasis,is the critical factor to determine the prognosis of NSCLC. Several clinical studies have shown that lymphatic invasion is a significant prognostic factor in NSCLC. Thus, it should be a new target in the diagnosis and therapy of NSCLC.
It is widely accepted that angiogenesis is essential for both tumor growth and metastasis. In the absence of local angiogenesis, tumors cannot grow beyond 2 mm3 . In addition, tumor angiogenesis has been reported to be associated with metastasis of primary tumors. Clinical studies in human cancer patients have also demonstrated that angiogenesis is associated with tumor metastasis and a poor prognosis. Furthermore, current studies have indicated that lymphangiogenesis is also associated with tumor metastasis. Thus, understanding and controlling angiogenesis and lymphangiogenesis could lead to effective strategies for cancer treatment.
However, the mechanisms of lymphatic metastasis have remained unclear for decades, mainly due to the lack of reliable markers for lymphatic vessels and identified lymphangiogenic growth factors in human cancers, and it makes our knowledge of the lymphatic system of lung cancer lags far behind that of the vascular system.
Recent advances in molecular biology have revealed mechanism of lymphatic spread in malignant tumors. The vascular endothelial growth factor (VEGF) gene family, which encodes five polypeptide growth factors, VEGF-A, -B, -C, -D,and -E, and their receptor family are particularly important a group of growth factors and receptors because of their angiogenic and lymphangiogenic properties that promote the growth and metastasis of neoplasma.
Vascular endothelial growth factor-C has been characterised as a lymphangiogenic and angiogenic growth factor and has been shown to signal through the receptors VEGFR-3 (also called Flt-4) and VEGFR-2. Among the vascular endothelial growth factor receptor (VEGFR) family members, Flt (fms-like tyrosine kinase)-4 is a receptor for VEGF-C and VEGF-D. Flt-4 is expressed on all of the embryonic endothelia, but its expression is largely restricted to the lymphatic endothelium in adult tissues. Recent studies have indicated that VEGFR-3, which has been proposed as a marker for lymphatic endothelial cells, is also expressed in a variety of human malignancies.
Experimental studies have revealed that tumors can actively induce the formation of lymphatic vessels (lymphangiogenesis)– via release of VEGF-C or VEGF-D, which activating of Flt-4, and thereby promote metastasis to draining lymph nodes. Moreover, inhibition of Flt-4 signaling can suppress tumor lymphangiogenesis and lymph node metastasis. Thus, Flt-4 can also be an important diagnostic and therapeutic target for treating a variety of malignant tumors.
In NSCLC, however, only a few clinical studies on VEGF-C (or VEGF-D), and Flt-4 expression have been reported, and clinical significance of VEGF-C (or VEGF-D), and Flt-4 expression on tumor cells and/or on endothelial cells remains controversial. Particularly, no study has documented a prognostic value of VEGF-C (or VEGF-D), and Flt-4 expression in endothelial cells. Therefore, we assessed the expression of VEGF-C and VEGFR-3 mRNA and protein in NSCLC by RT-PCR and Western Blot to demonstrate how they correlated with clinicopathological factors, including lymph node metastasis.
A total of 78 consecutive patients with pathological stage I-IIIA NSCLC who underwent complete tumor resection without any preoperative therapy at Beijing Chest Hospital between December 2006 to June 2007, and whose 234 histologic specimens are available for PCR and 171 histologic specimens for Western blot were prospectively studied.
Pathological stage was reevaluated and determined with the present TNM classification as revised in 1997. For analyses according to the different pathological type, different stage and different differentiation of cancer cells as well as other clinical features.
PCR detection result:
The relative contents of VEGF-C mRNA in cancer tissue and in paracancer were higher than those in normal tissues(VEGF-C mRNA 0.302±0.177, 0.209±0.131, 0.152±0.89) P<0.05,and the relative content of Flt-4 mRNA in cancer tissue was higher than that in normal tissue,(0.278±0.182 vs 0.181±0.128,P<0.05); the content in paracancer tissue was also higher than that in normal tissue,(0.199±0.128 vs 0.181±0.128, P> 0.05).
The relationship between VEGF-C or Flt-4 mRNA expression and clinicopathological features are shown that the expression level of VEGF-C mRNA and Flt-4 both in cancer tissue and paracancer tissue have significantly different in lymph node groups and stage groups. In paracancer group, the expression level of VEGF-C mRNA and Flt-4 has significantly different in histological grade group. There were no significant different in different age, different tumor position, different tumor size and different pathological types.
Westem blot detection:
171 histologic specimens in 57 patients were detected by Westem blot among 78 NSCLC, the protein level of VEGF-C in cancer tissue, paracancer tissue and normal tissue were 0.631±0.300,0.502±0.246, 0.531±0.286, respectively, there was significant different between cancer tissue and normal tissue, P=0.000. but for all the clinicopathological features, there were no significant different between age, gender, pathological types, stages, lymph node status and differentiation.
In conclusion, the present study gives evidence that VEGF-C and Flt-4 might play an important role in lymph node metastasis in NSCLC, Targeting the VEGF-C/Flt-4 may be therapeutically significant for certain types of tumours. Thus, the continued discovery and characterization of factors that regulate VEGF-C or Flt-4 will be essential for developing new therapies that limit the spread of cancer.
引文
[1]. Carney DN. Lung cancer: time to move on from chemotherapy. N Engl J Med 2002; 346:126-8.
[2]. Jemal A, Siegel R, Ward E et al. Cancer statistics 2006. CA Cancer J. Clin. 2006; 56: 106–30.
[3]. Alberts WM. Lung cancer guidelines. Chest 2003; 123:1S–2S.
[4]. Mountain CF. Revisions in the international system for staging lung cancer. Chest 1997; 111: 1710–17.
[5]. Miller DL, Rowland CM, Deschamps MC, et al. Surgical treatment of non-small cell lung cancer 1cm or less in diameter. Ann Thorac Surg, 2002, 73:1545-15
[6]. Stacker SA, Caeser C, Baldwin ME, et al. VEGF-D promotes the metastatic spread of tumor cells via the lymphatics. Nature Med, 2001, 7:186-91
[7]. Skobe M, Hawighorst T, Jackson DG, et al. Induction of tumor lymphangiogenesis by VEGF-C promotes breast cancer metastasis. Nature Med, 2001,7:192-8
[8].Stentan J, Christoph W, Thomas J, et al. Vascular endothelial growth factor-D and its receptor VEGFR-3. Two novel independent prognostic markers in gastric adenocarcinoma. J Clin Oncol, 2006, 24:228-40
[9]. White JD, Hewett PW, Kostige D, et al. Vascular endothelial growth factor-D expression as an independent prognostic marker for survival in colorectal carcinoma. Cancer Res, 2002, 62:1669-75
[10]. Yokoyama Y, Charnock-Jones DS, Licence D, et al. Vascular endothelial growth factor-D is an independent prognostic factor in epithelial ovarian carcinoma. Br J Cancer, 2003, 88:237-44
[11].Nakamura Y, Yasuoka H, tsujimoto M, et al. Prognosticsignificance of Vascular endothelial growth factor-D in breast carcinoma with long-term follow-up. Clin Cancer Res, 2003, 9:716-21
[12]. Kajita T, Ohta Y, Kimura K, et al. The expression of vascular endothelial growth factor C and its receptors in non-small cell lung cancer. Br J Cancer,2001,85:255–60
[13]. Arinaga M, Noguchi T, Takeno S, et al. Clinical significance of vascular endothelial growth factor C and vascular endothelial growth factor receptor-3 in patients with non-small cell lung carcinoma. Cancer,2003, 97: 457-64
[14]. Ogawa E, Takenaka K, Yanagihara K, et al. Clinical significance of VEGF-C status in tumour cells and stromal macrophages in non-small cell lung cancer patients. Br J Cancer,2004, 91:498–503
[15].Veikkola T, Karkkainen M,Claesson-Welsh,et al. Regulation of angiogenesis via vascular endothelia growth factor receptors. Cancer Res, 2000, 60:203-12.
[16].杨艳,葛荣明.VEGF和VEGF-C在喉癌中的表达及临床意义.临床耳鼻喉科杂志,2002,16(12):650-2.
[17]. Tsurusaki T,Kanda S,Sakai H,et al.Vascular endothelial growth factor-C expression in human prostatic carcinoma and its relationship to lymph node metastasis. Br J Cancer, 1999,80:309-13.
[18]. Niki T, Iba S, Tokunou M, ET AL. Expression of vascular endothelial growth factors A, B, C, and D and their relationships to lymph node status in lung adenocarcinoma. Clin Cancer Res,2000, 6: 2431-9
[19].Kinoshita J,Kitamura K,Kabashima A,et al. Clinical significance of vascular endothelial growth factor-C(VEGF-C)in breast cancer. Breast cancer Res. Treat,2001,66(2):159-164.
[20].Kawakami M, Furuhata T, Kimura Y, et al. Quantification of vascular endothelial growth factor-C and its receptor-3 messenger RNAwith real-time quantitative polymerase chain reaction as a predictor of lymph node metastasis in human colorectal cancer. Surgery, 2003, 133: 300–8
[21]. Kitadai Y, Amioka T, Haruma K, et al. Clinicopathological significance of vascular endothelial growth factor (VEGF)-C in human esophageal squamous cell carcinomas. Int J Cancer, 2001, 93: 662–6
[22]. Neuchrist C, Erovic BM, Handisurya A, et al. Vascular endothelial growth factor C and vascular endothelial growth factor receptor-3 expression in squamous cell carcinomas of head and neck. Head Neck,2003, 25:464–74
[23]. Hashimoto I, Kodama J, Seki N, et al. Vascular endothelial growth factor-C expression and its relationship to pelvic lymph node status in invasive cervical cancer. Br J Cancer,2001, 85: 93–7
[24] Kurebayashi J, Otsuki T, et al . Expression of vascular endothelial growth factor (VEGF) family members in breast cancer[J] . Jpn J Cancer Res, 1999, 90(9): 977-81.
[25]. Van Trappen PO, Steele D, Lowe DG, et al. Expression of vascular endothelial growth factor VEGF-C and VEGF-D, and their receptor VEGFR-3, during different stages of cervical carcinogenesis. J Pathol 201: 544–54
[26].Akagi K, Ikeda Y, Miyazaki M, et al. Vascular endothelial growth factor-C (VEGF-C) expression in human colorectal cancer tissues. Br J Cancer,2000, 83: 887–91
[27]. Juttner S, Wissmann C, Jons T, et al. Vascular endothelial growth factor-D and its receptor VEGFR-3: two novel independent prognostic markers in gastric adenocarcinoma. J Clin Oncol,2006, 24: 228–40
[28]. Su JL, Yang PC, Shih JY, et al. The VEGF-C/VEGFR-3 axis promotes invasion and metastasis of cancer cells. Cancer Cell,2006, 9: 209–23
[29]. Witte D, Thomas A, Ali N, et al. Expression of the vascular endothelial growth factor receptor-3 (VEGFR-3) and its ligand VEGF-C in human colorectal adenocarcinoma. Anticancer Res,2002, 22: 1463–6
[30].Li Q, Dong X, Gu W, et al. Clinical significance of coexpression of VEGF-C and VEGFR-3 in non-small cell lung cancer. Chin Med J (England),2003, 116: 727–730
[31]. Nathanson SD. Insights into the mechanisms of lymph node metastases. Cancer,2003,98:413—23.
[32].Padera TP, Kadambi A, di Tomaso E, et al. Lymphatic metastasis in the absence of functional intratumor lymphatics. Science, 2002, 296:1883–6
[33].Gombos Z, Xu X, Chu CS, et al. Peritumoral lymphatic vessel density and vascular endothelial growth factor C expression in early-stage squamous cell carcinoma of the uterine cervix. Clin Cancer Res, 2005, 11:8364–71
[34]. Cao Y. Emerging mechanisms of tumor lymphangiogenesis and lymphatic metastasis. Nat Rev Cancer 2005;5:1—9.
[35]. Stacker SA, Achen MG, Jussila L, et al. Lymphangiogenesis and cancer metastases. Nat Rev Cancer 2002;2:573—83.
[36]. Takizawa1 H, Kondo K, Fujino1 H, et al. The balance of VEGF-C and VEGFR-3 mRNA is a predictor of lymph node metastasis in non-small cell lung cancer, Br J Cancer,2006,95:75-9
[37]. Chen F, Takenaka K, Ogawa E, et al. Flt-4–Positive Endothelial Cell Density and Its Clinical Significance in Non–Small Cell Lung Cancer. Clin Cancer Res, 2004, 10:8548-53
[38] Saintignya P, Kambouchnerc M, Madani L,et al. Vascular endothelial growth factor-C and its receptor VEGFR-3 in non-small-cell lung cancer: Concurrent expression in cancer cells from primary tumourand metastatic lymph node. Lung cancer,2007,58:205-13
[1] Clifton F, Mountain CF. Revisions in the international system for staging lung cancer. Chest 1997;111:1711—7.
[2] Suzuki K, Nagai K, Yaoshida J, et al. Conventional clinico-pathologic prognosis factors in surgically resected non-small cell lung carcinoma. Cancer 1999;86:1976-84
[3] Macchiarini P, Fontanini G, hardin JM, et al. Blood vessel invasion by tumor cells predicts recurrence in completely resected T1N0M0 non-small cell lung cancer. J Thorac Cardiovasc Surg 1993;106:80-9
[4] Brechot JM, Chevret S, Charpentier MC, et al. Blood vessel and lymphatic vessel invasion in resected non-small cell lung carcinoma, Correlation with TNM stage and disease free and overall survival. Cancer 1996;78:2111-8
[5] Pepper MS. Lymphangiogenesis and tumor metastasis : myth or reality ? Clin Cancer Res 2001;(7) :462-8
[6] Skobe M,Detmar M. Structure ,function ,and molecular control of the skin lymphatic system. J Investig Dermatol Symp Proc. 2000 ;(5):14-9
[7] Folkman J, Watson K, Ingbher D, Hanahan D. Induction of angiogenesis during the transition from hyperplasia to neoplasia. Nature 1989;339:58—9.
[8] Folkman J. What is the evidence that tumours are angiogenesis-dependent? J Natl Cancer Inst 1991;82:4—6.
[9] Karpanen T , Egeblad M , Karkkainen MJ ,et al. Vascular endothelial growth factor C promotes tumour lymphangiogenesis and intralymphatic tumour growth. Cancer Res ,2001 ,61 (5):1786-90.
[10] Duff SE , Li C , Jeziorska M , et al. Vascular endothelial growth factors C and D and lymphangiogenesis in gastrointestinal tract malignancy.Br J Cancer , 2003;89 (3) :426-30.
[11] Niki T,Iba S, Tokumou M , et al. Expression of vascular endothelial growth factors A, B, C, and D, and their relationships to lymph node status in lung adenocarcinoma. Clin Cancer Res,2000;6:2431-9.
[12] Saharinen P, Petrova TV. Molecular regulation of lymphangiogenesis. Ann N Y Acad Sci 2004;1014∶76-87.
[13] Tanigaki Y, Nagashima Y, Kitamura Y, et al. The expression of vascular endothelial growth factor-A and C, and receptors 1 and 3: correlation with lymph node metastasis and prognosis in tongue squamous cell carcinoma. Int J Mol Med 2004;14:389-95.
[14] Zeng Y, Opeskin K, Baldwin ME, et al. Expression of vascular endothelial growth factor receptor-3 by lymphatic endothelial cells is associated with lymph node metastasis in prostate cancer. Clin Cancer Res 2004;10∶5137- 44.
[15] Kazama S, Kitayma J, Watanabe T, et al. Expression pattern of vascular endothelial growth factor-C in human colorectal normal mucosa and neoplastic mucosa. Hepatogastroenterolgy 2004;51:391-5.
[16] Shimizu K, Kubo H, Yamaguchi K, et al. Suppression of VEGFr-3 signaling inhibits lymph node metastasis in gastric cancer. Cancer Sci 2004;95:328-33.
[17] Hashimoto I, Kodama J, Seki N, et al. Vascular endothelial growth factor-C expression and its relationship to pelvic lymph node status in invasive cervical cancer. Br J Cancer 2001;85:93-7.
[18] Furudio A,Tanaka S, Haruma K, et al. Clinical significance of vascular endothelial growth factor-C expression and angiogenesis at the deepest invasive advanced colorectal carcinoma. Oncology 2002;62:157-66
[19] Akagi K,IkedaY,SumiyoshiY,et al. Estimation of angiogenesis with anti CD-105 immunostaining in the process of colorectal cancer development.Surgery 2002,131:S 109-13
[20] Achen M G, Jeltsch M, Kukk E , et al . Vascular endothelial growth factor D (VEGF-D) is a ligand for the tyrosine kinases VEGF receptor 2 (Flk1) and VEGF receptor 3 ( Flt4) [J] . Proc Natl Acad Sci USA , 1998 ,95(2): 548 - 53
[21] He Y, Kozaki K, Karpanen T, et al . Suppression of tumor lymphangiogenesis and lymph node metastasis by blocking vascular endothelial growth factor receptor 3 signaling [J] . J Natl Cancer Inst , 2002, 94 (11): 819 -25
[22] Takahashi M, Yoshimoto T, Kubo H. Molecular mechanisms of lymhangiogenesis.Int J Hematol 2004; 80:29-34.
[23] Tille JC, Nisato R, Pepper M. Lymphangiogenesis and tumor metastasis.Novartis Found Symp,2004,256:112-31;discussion 132-6, 259-69
[24] Hanrahan V, Currie MJ, Gunningham DP, et al. The angiogenic switch forvascular endothelial growth factor (VEGF-A, VEGF-B, VEGF-C, and VEGF-D) in the adenoma carcinoma sequence during colorectal cancer progression. J Pathol, 2003 200:183-94.
[25] Van Trappen PO, Steele D, Lowe DG, et al. Expression of vascular endothelial growth factor (VEGF)-C and VEGF-D, and their receptor VEGFR-3, during different stages of cervical carcinogenesis. J Pathol, 2003 201:544-54.
[26] Clarijs R, Schalkwijk L, Hofmann UB, et al. Inductionof vascular endothelial growth factor-3 expression on tumor microvasculature as a new progression marker in human cutaneous melanoma. Cancer Res, 2002 62:7059-65.
[27] Ebata N, Nodasaka Y, Sawa Y, et al. Desmoplakin as a specific marker of lymphatic vessels.[J] Microvasc Res, 2001, 61(1):40-48.
[28] Fukuda H, Yamada T, Kamata S, et al . Immunohistochemical identification of initial lymphatics: the contour and distribution pattern of initial lymphatics in the human foreskin of the penis. J Nippon Hinyokika Gakkai Zasshi , 2000, 91 (2): 49-54.
[29] Banerji S, Ni J,Wang SX, Et al. LYVE-1, a new homologue of the CD44 glycoprotein, is a lymph-specific receptor for hyaluronan.;J Cell Biol.1999,144(4:789-801
[30] Fraser JR, Kimpton WG, Laurent TC, et al. Uptake and degradation of hyaluronan in lymphatic tissue. Biochem J 1998;256:153–8.
[31] Laurent TC, Fraser JR. Hyaluronan. FASEB J 1992;6:2397–404.
[32] Cueni LN, Detmar M. New insights into the molecular control of the lymphatic vascular system and its role in disease. J Invest Dermatol 2006; 126:2167–2177.
[33] Kajita T ,Ohta Y,Kimura K, et al . The expression of vascular endothelial growth factor C and its receptors in non-small cell lung cancer[J] .Br J Cancer ,2001 ,85 (2) :255–260.
[34] Arinaga M,Noguchi T ,Takeno S , et al . Clinical significance of vascular endothelial growth factor C and vascular endothelial growth factor receptor 3 in patients with non-small cell lung carcinoma [J] . Cancer ,2003 ,97 (2) :457–464.
[2]. Jemal A, Siegel R, Ward E et al. Cancer statistics 2006. CA Cancer J. Clin. 2006; 56: 106–30.
[3]. Alberts WM. Lung cancer guidelines. Chest 2003; 123:1S–2S.
[4]. Mountain CF. Revisions in the international system for staging lung cancer. Chest 1997; 111: 1710–17.
[5]. Miller DL, Rowland CM, Deschamps MC, et al. Surgical treatment of non-small cell lung cancer 1cm or less in diameter. Ann Thorac Surg, 2002, 73:1545-15
[6]. Stacker SA, Caeser C, Baldwin ME, et al. VEGF-D promotes the metastatic spread of tumor cells via the lymphatics. Nature Med, 2001, 7:186-91
[7]. Skobe M, Hawighorst T, Jackson DG, et al. Induction of tumor lymphangiogenesis by VEGF-C promotes breast cancer metastasis. Nature Med, 2001,7:192-8
[8].Stentan J, Christoph W, Thomas J, et al. Vascular endothelial growth factor-D and its receptor VEGFR-3. Two novel independent prognostic markers in gastric adenocarcinoma. J Clin Oncol, 2006, 24:228-40
[9]. White JD, Hewett PW, Kostige D, et al. Vascular endothelial growth factor-D expression as an independent prognostic marker for survival in colorectal carcinoma. Cancer Res, 2002, 62:1669-75
[10]. Yokoyama Y, Charnock-Jones DS, Licence D, et al. Vascular endothelial growth factor-D is an independent prognostic factor in epithelial ovarian carcinoma. Br J Cancer, 2003, 88:237-44
[11].Nakamura Y, Yasuoka H, tsujimoto M, et al. Prognosticsignificance of Vascular endothelial growth factor-D in breast carcinoma with long-term follow-up. Clin Cancer Res, 2003, 9:716-21
[12]. Kajita T, Ohta Y, Kimura K, et al. The expression of vascular endothelial growth factor C and its receptors in non-small cell lung cancer. Br J Cancer,2001,85:255–60
[13]. Arinaga M, Noguchi T, Takeno S, et al. Clinical significance of vascular endothelial growth factor C and vascular endothelial growth factor receptor-3 in patients with non-small cell lung carcinoma. Cancer,2003, 97: 457-64
[14]. Ogawa E, Takenaka K, Yanagihara K, et al. Clinical significance of VEGF-C status in tumour cells and stromal macrophages in non-small cell lung cancer patients. Br J Cancer,2004, 91:498–503
[15].Veikkola T, Karkkainen M,Claesson-Welsh,et al. Regulation of angiogenesis via vascular endothelia growth factor receptors. Cancer Res, 2000, 60:203-12.
[16].杨艳,葛荣明.VEGF和VEGF-C在喉癌中的表达及临床意义.临床耳鼻喉科杂志,2002,16(12):650-2.
[17]. Tsurusaki T,Kanda S,Sakai H,et al.Vascular endothelial growth factor-C expression in human prostatic carcinoma and its relationship to lymph node metastasis. Br J Cancer, 1999,80:309-13.
[18]. Niki T, Iba S, Tokunou M, ET AL. Expression of vascular endothelial growth factors A, B, C, and D and their relationships to lymph node status in lung adenocarcinoma. Clin Cancer Res,2000, 6: 2431-9
[19].Kinoshita J,Kitamura K,Kabashima A,et al. Clinical significance of vascular endothelial growth factor-C(VEGF-C)in breast cancer. Breast cancer Res. Treat,2001,66(2):159-164.
[20].Kawakami M, Furuhata T, Kimura Y, et al. Quantification of vascular endothelial growth factor-C and its receptor-3 messenger RNAwith real-time quantitative polymerase chain reaction as a predictor of lymph node metastasis in human colorectal cancer. Surgery, 2003, 133: 300–8
[21]. Kitadai Y, Amioka T, Haruma K, et al. Clinicopathological significance of vascular endothelial growth factor (VEGF)-C in human esophageal squamous cell carcinomas. Int J Cancer, 2001, 93: 662–6
[22]. Neuchrist C, Erovic BM, Handisurya A, et al. Vascular endothelial growth factor C and vascular endothelial growth factor receptor-3 expression in squamous cell carcinomas of head and neck. Head Neck,2003, 25:464–74
[23]. Hashimoto I, Kodama J, Seki N, et al. Vascular endothelial growth factor-C expression and its relationship to pelvic lymph node status in invasive cervical cancer. Br J Cancer,2001, 85: 93–7
[24] Kurebayashi J, Otsuki T, et al . Expression of vascular endothelial growth factor (VEGF) family members in breast cancer[J] . Jpn J Cancer Res, 1999, 90(9): 977-81.
[25]. Van Trappen PO, Steele D, Lowe DG, et al. Expression of vascular endothelial growth factor VEGF-C and VEGF-D, and their receptor VEGFR-3, during different stages of cervical carcinogenesis. J Pathol 201: 544–54
[26].Akagi K, Ikeda Y, Miyazaki M, et al. Vascular endothelial growth factor-C (VEGF-C) expression in human colorectal cancer tissues. Br J Cancer,2000, 83: 887–91
[27]. Juttner S, Wissmann C, Jons T, et al. Vascular endothelial growth factor-D and its receptor VEGFR-3: two novel independent prognostic markers in gastric adenocarcinoma. J Clin Oncol,2006, 24: 228–40
[28]. Su JL, Yang PC, Shih JY, et al. The VEGF-C/VEGFR-3 axis promotes invasion and metastasis of cancer cells. Cancer Cell,2006, 9: 209–23
[29]. Witte D, Thomas A, Ali N, et al. Expression of the vascular endothelial growth factor receptor-3 (VEGFR-3) and its ligand VEGF-C in human colorectal adenocarcinoma. Anticancer Res,2002, 22: 1463–6
[30].Li Q, Dong X, Gu W, et al. Clinical significance of coexpression of VEGF-C and VEGFR-3 in non-small cell lung cancer. Chin Med J (England),2003, 116: 727–730
[31]. Nathanson SD. Insights into the mechanisms of lymph node metastases. Cancer,2003,98:413—23.
[32].Padera TP, Kadambi A, di Tomaso E, et al. Lymphatic metastasis in the absence of functional intratumor lymphatics. Science, 2002, 296:1883–6
[33].Gombos Z, Xu X, Chu CS, et al. Peritumoral lymphatic vessel density and vascular endothelial growth factor C expression in early-stage squamous cell carcinoma of the uterine cervix. Clin Cancer Res, 2005, 11:8364–71
[34]. Cao Y. Emerging mechanisms of tumor lymphangiogenesis and lymphatic metastasis. Nat Rev Cancer 2005;5:1—9.
[35]. Stacker SA, Achen MG, Jussila L, et al. Lymphangiogenesis and cancer metastases. Nat Rev Cancer 2002;2:573—83.
[36]. Takizawa1 H, Kondo K, Fujino1 H, et al. The balance of VEGF-C and VEGFR-3 mRNA is a predictor of lymph node metastasis in non-small cell lung cancer, Br J Cancer,2006,95:75-9
[37]. Chen F, Takenaka K, Ogawa E, et al. Flt-4–Positive Endothelial Cell Density and Its Clinical Significance in Non–Small Cell Lung Cancer. Clin Cancer Res, 2004, 10:8548-53
[38] Saintignya P, Kambouchnerc M, Madani L,et al. Vascular endothelial growth factor-C and its receptor VEGFR-3 in non-small-cell lung cancer: Concurrent expression in cancer cells from primary tumourand metastatic lymph node. Lung cancer,2007,58:205-13
[1] Clifton F, Mountain CF. Revisions in the international system for staging lung cancer. Chest 1997;111:1711—7.
[2] Suzuki K, Nagai K, Yaoshida J, et al. Conventional clinico-pathologic prognosis factors in surgically resected non-small cell lung carcinoma. Cancer 1999;86:1976-84
[3] Macchiarini P, Fontanini G, hardin JM, et al. Blood vessel invasion by tumor cells predicts recurrence in completely resected T1N0M0 non-small cell lung cancer. J Thorac Cardiovasc Surg 1993;106:80-9
[4] Brechot JM, Chevret S, Charpentier MC, et al. Blood vessel and lymphatic vessel invasion in resected non-small cell lung carcinoma, Correlation with TNM stage and disease free and overall survival. Cancer 1996;78:2111-8
[5] Pepper MS. Lymphangiogenesis and tumor metastasis : myth or reality ? Clin Cancer Res 2001;(7) :462-8
[6] Skobe M,Detmar M. Structure ,function ,and molecular control of the skin lymphatic system. J Investig Dermatol Symp Proc. 2000 ;(5):14-9
[7] Folkman J, Watson K, Ingbher D, Hanahan D. Induction of angiogenesis during the transition from hyperplasia to neoplasia. Nature 1989;339:58—9.
[8] Folkman J. What is the evidence that tumours are angiogenesis-dependent? J Natl Cancer Inst 1991;82:4—6.
[9] Karpanen T , Egeblad M , Karkkainen MJ ,et al. Vascular endothelial growth factor C promotes tumour lymphangiogenesis and intralymphatic tumour growth. Cancer Res ,2001 ,61 (5):1786-90.
[10] Duff SE , Li C , Jeziorska M , et al. Vascular endothelial growth factors C and D and lymphangiogenesis in gastrointestinal tract malignancy.Br J Cancer , 2003;89 (3) :426-30.
[11] Niki T,Iba S, Tokumou M , et al. Expression of vascular endothelial growth factors A, B, C, and D, and their relationships to lymph node status in lung adenocarcinoma. Clin Cancer Res,2000;6:2431-9.
[12] Saharinen P, Petrova TV. Molecular regulation of lymphangiogenesis. Ann N Y Acad Sci 2004;1014∶76-87.
[13] Tanigaki Y, Nagashima Y, Kitamura Y, et al. The expression of vascular endothelial growth factor-A and C, and receptors 1 and 3: correlation with lymph node metastasis and prognosis in tongue squamous cell carcinoma. Int J Mol Med 2004;14:389-95.
[14] Zeng Y, Opeskin K, Baldwin ME, et al. Expression of vascular endothelial growth factor receptor-3 by lymphatic endothelial cells is associated with lymph node metastasis in prostate cancer. Clin Cancer Res 2004;10∶5137- 44.
[15] Kazama S, Kitayma J, Watanabe T, et al. Expression pattern of vascular endothelial growth factor-C in human colorectal normal mucosa and neoplastic mucosa. Hepatogastroenterolgy 2004;51:391-5.
[16] Shimizu K, Kubo H, Yamaguchi K, et al. Suppression of VEGFr-3 signaling inhibits lymph node metastasis in gastric cancer. Cancer Sci 2004;95:328-33.
[17] Hashimoto I, Kodama J, Seki N, et al. Vascular endothelial growth factor-C expression and its relationship to pelvic lymph node status in invasive cervical cancer. Br J Cancer 2001;85:93-7.
[18] Furudio A,Tanaka S, Haruma K, et al. Clinical significance of vascular endothelial growth factor-C expression and angiogenesis at the deepest invasive advanced colorectal carcinoma. Oncology 2002;62:157-66
[19] Akagi K,IkedaY,SumiyoshiY,et al. Estimation of angiogenesis with anti CD-105 immunostaining in the process of colorectal cancer development.Surgery 2002,131:S 109-13
[20] Achen M G, Jeltsch M, Kukk E , et al . Vascular endothelial growth factor D (VEGF-D) is a ligand for the tyrosine kinases VEGF receptor 2 (Flk1) and VEGF receptor 3 ( Flt4) [J] . Proc Natl Acad Sci USA , 1998 ,95(2): 548 - 53
[21] He Y, Kozaki K, Karpanen T, et al . Suppression of tumor lymphangiogenesis and lymph node metastasis by blocking vascular endothelial growth factor receptor 3 signaling [J] . J Natl Cancer Inst , 2002, 94 (11): 819 -25
[22] Takahashi M, Yoshimoto T, Kubo H. Molecular mechanisms of lymhangiogenesis.Int J Hematol 2004; 80:29-34.
[23] Tille JC, Nisato R, Pepper M. Lymphangiogenesis and tumor metastasis.Novartis Found Symp,2004,256:112-31;discussion 132-6, 259-69
[24] Hanrahan V, Currie MJ, Gunningham DP, et al. The angiogenic switch forvascular endothelial growth factor (VEGF-A, VEGF-B, VEGF-C, and VEGF-D) in the adenoma carcinoma sequence during colorectal cancer progression. J Pathol, 2003 200:183-94.
[25] Van Trappen PO, Steele D, Lowe DG, et al. Expression of vascular endothelial growth factor (VEGF)-C and VEGF-D, and their receptor VEGFR-3, during different stages of cervical carcinogenesis. J Pathol, 2003 201:544-54.
[26] Clarijs R, Schalkwijk L, Hofmann UB, et al. Inductionof vascular endothelial growth factor-3 expression on tumor microvasculature as a new progression marker in human cutaneous melanoma. Cancer Res, 2002 62:7059-65.
[27] Ebata N, Nodasaka Y, Sawa Y, et al. Desmoplakin as a specific marker of lymphatic vessels.[J] Microvasc Res, 2001, 61(1):40-48.
[28] Fukuda H, Yamada T, Kamata S, et al . Immunohistochemical identification of initial lymphatics: the contour and distribution pattern of initial lymphatics in the human foreskin of the penis. J Nippon Hinyokika Gakkai Zasshi , 2000, 91 (2): 49-54.
[29] Banerji S, Ni J,Wang SX, Et al. LYVE-1, a new homologue of the CD44 glycoprotein, is a lymph-specific receptor for hyaluronan.;J Cell Biol.1999,144(4:789-801
[30] Fraser JR, Kimpton WG, Laurent TC, et al. Uptake and degradation of hyaluronan in lymphatic tissue. Biochem J 1998;256:153–8.
[31] Laurent TC, Fraser JR. Hyaluronan. FASEB J 1992;6:2397–404.
[32] Cueni LN, Detmar M. New insights into the molecular control of the lymphatic vascular system and its role in disease. J Invest Dermatol 2006; 126:2167–2177.
[33] Kajita T ,Ohta Y,Kimura K, et al . The expression of vascular endothelial growth factor C and its receptors in non-small cell lung cancer[J] .Br J Cancer ,2001 ,85 (2) :255–260.
[34] Arinaga M,Noguchi T ,Takeno S , et al . Clinical significance of vascular endothelial growth factor C and vascular endothelial growth factor receptor 3 in patients with non-small cell lung carcinoma [J] . Cancer ,2003 ,97 (2) :457–464.