Significance of lymphangiogenesis in primary tumor and draining lymph nodes during lymphatic metastasis of pancreatic head cancer

Kurahara, Hiroshi; Takao, Sonshin; Shinchi, Hiroyuki; Maemura, Kousei; Mataki, Yuko; Shimada, Masahiko; Hayashi, Takuma; Kuwahata, Taisaku; Minami, Koji; Ueno, S.; Natsugoe, Shoji

doi:10.1002/jso.21744

Cited by 27 publications

(23 citation statements)

References 31 publications

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“…We can predict a similar phenomenon in colorectal cancer as the level of VEGF-C was shown to be elevated in the blood serum of patients with colorectal cancer [19]. It has been hypothesized that lymph node lymph vessels can act as a metastatic niche for cancer cells [7], [8], [20], [21] and facilitate further metastatic transformation of the tumor cells. This might lead to therapy-resistant metastatic cancer and is therefore responsible for poor patient prognosis.…”

Section: Discussionmentioning

confidence: 57%

“…Therefore, efforts have been made to uncover the mechanisms of lymph node metastasis. It has been suggested that the induction of lymphangiogenesis in the primary tumor and in lymph nodes significantly contributes to tumor metastases [7], [8]. In this study we have validated lymphangiogenesis in regional lymph nodes as a predictor for poor prognosis and facilitator for distant metastasis in a cohort of neoadjuvant treated advanced rectal cancer patients.…”

Section: Introductionmentioning

confidence: 66%

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Lymphangiogenesis in Regional Lymph Nodes Is an Independent Prognostic Marker in Rectal Cancer Patients after Neoadjuvant Treatment

et al. 2011

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One of the major prognostic factors in rectal cancer is lymph node metastasis. The formation of lymph node metastases is dependent on the existence of a premetastatic niche. An important factor preceding metastasis are lymph vessels which are located in the lymph node. Accordingly, the occurrence of intranodal lymphangiogenesis is thought to indicate distant metastasis and worse prognosis. To evaluate the significance of lymph node lymphangiogenesis, we studied formalin fixed, paraffin embedded adenocarcinomas and regional lymph nodes of 203 rectal cancer patients who were treated with neoadjuvant radiochemotherapy and consecutive curative surgery with cancer free surgical margins (R0). Regional lymph node lymph vessels were detected by immunohistochemistry for podoplanin (D2-40). Our results show that the presence of lymphatic vessels in regional lymph nodes significantly affects the disease-free survival in univariate and multivariate analyses. In contrast, there was no correlation between peritumoral or intratumoral lymph vessel density and prognosis. Indeed, our study demonstrates the importance of lymphangiogenesis in regional lymph nodes after neoadjuvant radiochemotherapy and consecutive surgery as an independent prognostic marker. Staining for intranodal lymphangiogenesis and methods of intravital imaging of lymphangiogenesis and lymphatic flow may be a useful strategy to predict long-term outcome in rectal cancer patients. Furthermore, addition of VEGF-blocking agents to standardized neoadjuvant treatment schemes might be indicated in advanced rectal cancer.

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Section: Discussionmentioning

confidence: 57%

Section: Introductionmentioning

confidence: 66%

Lymphangiogenesis in Regional Lymph Nodes Is an Independent Prognostic Marker in Rectal Cancer Patients after Neoadjuvant Treatment

et al. 2011

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“…Increased lymphangiogenesis in pancreatic tumors or their draining nodes is generally believed to relate directly to the extent of lymphatic involvement [52, 53]. However, some studies suggest that intratumoral lymphatic vessel density (LVD) is not associated with lymphatic invasion or metastasis [11, 54].…”

Section: Discussionmentioning

confidence: 99%

Combined targeting of TGF-β, EGFR and HER2 suppresses lymphangiogenesis and metastasis in a pancreatic cancer model

et al. 2016

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Pancreatic ductal adenocarcinomas (PDAC) are aggressive with frequent lymphatic spread. By analysis of data from The Cancer Genome Atlas, we determined that ∼35% of PDACs have a pro-angiogenic gene signature. We now show that the same PDACs exhibit increased expression of lymphangiogenic genes and lymphatic endothelial cell (LEC) markers, and that LEC abundance in human PDACs correlates with endothelial cell microvessel density. Lymphangiogenic genes and LECs are also elevated in murine PDACs arising in the KRC (mutated Kras; deleted RB) and KIC (mutated Kras; deleted INK4a) genetic models. Moreover, pancreatic cancer cells (PCCs) derived from KRC tumors express and secrete high levels of lymphangiogenic factors, including the EGF receptor ligand, amphiregulin. Importantly, TGF-β1 increases lymphangiogenic genes and amphiregulin expression in KRC PCCs but not in murine PCCs that lack SMAD4, and combinatorial targeting of the TGF-β type I receptor (TβRI) with LY2157299 and EGFR/HER2 with lapatanib suppresses tumor growth and metastasis in a syngeneic orthotopic model, and attenuates tumor lymphangiogenesis and angiogenesis while reducing lymphangiogenic genes and amphiregulin and enhancing apoptosis. Therefore, this combination could be beneficial in PDACs with lymphangiogenic or angiogenic gene signatures.

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“…Studies of human pancreatic cancer tissues have identified a role for TALA in lymph node metastasis and patient outcomes. Kurahara, et al [154], found that high lymphatic vessel density (LVD) in PDAC head tumors predicted increased lymph node metastasis and decreased survival. They also showed increased LVD within metastatic lymph nodes [154].…”

Section: Lymphangiogenesismentioning

confidence: 99%

“…Kurahara, et al [154], found that high lymphatic vessel density (LVD) in PDAC head tumors predicted increased lymph node metastasis and decreased survival. They also showed increased LVD within metastatic lymph nodes [154]. Wang, et al , found that increased peritumoral LVD in human pancreatic carcinoma tissues correlated with unfavorable tumor differentiation status, increased LVI, and more lymph node metastasis, while this was not the case for intratumoral LVD [53].…”

Section: Lymphangiogenesismentioning

confidence: 99%

The lymphatic system and pancreatic cancer

2016

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This review summarizes current knowledge of the biology, pathology and clinical understanding of lymphatic invasion and metastasis in pancreatic cancer. We discuss the clinical and biological consequences of lymphatic invasion and metastasis, including paraneoplastic effects on immune responses and consider the possible benefit of therapies to treat tumors that are localized to lymphatics. A review of current techniques and methods to study interactions between tumors and lymphatics is presented.

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Significance of lymphangiogenesis in primary tumor and draining lymph nodes during lymphatic metastasis of pancreatic head cancer

Abstract: Lymphangiogenesis in primary tumors and draining lymph nodes is essential for efficient spread of tumor cells through the lymphatic system. Thus, inhibition of lymphangiogenesis could limit lymphatic dissemination of tumor cells.

Cited by 27 publications

References 31 publications

Lymphangiogenesis in Regional Lymph Nodes Is an Independent Prognostic Marker in Rectal Cancer Patients after Neoadjuvant Treatment

Lymphangiogenesis in Regional Lymph Nodes Is an Independent Prognostic Marker in Rectal Cancer Patients after Neoadjuvant Treatment

Combined targeting of TGF-β, EGFR and HER2 suppresses lymphangiogenesis and metastasis in a pancreatic cancer model

The lymphatic system and pancreatic cancer

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