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Pickett L, Dunne M, Monaghan O, Grogan L, Breathnach O, Walsh TN. Oesophageal cancer metastases: An observational study of a more aggressive approach. World J Gastrointest Surg 2022; 14:997-1007. [PMID: 36185560 PMCID: PMC9521477 DOI: 10.4240/wjgs.v14.i9.997] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2021] [Revised: 05/04/2022] [Accepted: 08/31/2022] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND The prognosis for oesophageal carcinoma is poor, but once distant metastases emerge the prognosis is considered hopeless. There is no consistent protocol for the early identification and aggressive management of metastases.
AIM To examine the outcome of a policy of active postoperative surveillance with aggressive treatment of confirmed metastases.
METHODS A prospectively maintained database of 205 patients diagnosed with oesophageal carcinoma between 1998 and 2019 and treated with curative intent was interrogated for patients with metastases, either at diagnosis or on follow-up surveillance and treated for cure. This cohort was compared with incomplete clinical responders to neoadjuvant chemoradiotherapy (nCRT) who subsequently underwent surgery on their primary tumour. Overall survival was estimated using the Kaplan-Meier method, and the log-rank test was used to compare survival differences between groups.
RESULTS Of 205 patients, 11 (5.4%) had metastases treated for cure (82% male; median age 60 years; 9 adenocarcinoma and 2 squamous cell carcinomas). All had undergone neoadjuvant chemotherapy or chemoradiotherapy, followed by surgery in all but 1 case. Of the 11 patients, 4 had metastatic disease at diagnosis, of whom 3 were successfully downstaged with nCRT before definitive surgery; 2 of these 4 also developed oligometastatic recurrence and were treated with curative intent. Following definitive treatment, 7 had treatment for metachronous oligometastatic disease; 5 of whom underwent metastasectomy (adrenal × 2; lung × 2; liver × 1). The median overall survival was 10.9 years [95% confidence interval (CI): 0.7-21.0 years], which was statistically significantly longer than incomplete clinical responders undergoing surgery on the primary tumour without metastatic intervention [n = 62; median overall survival = 1.9 (95%CI: 1.1-2.7; P = 0.012]. The cumulative proportion surviving 1, 3, and 5 years was 100%, 91%, and 61%, respectively compared to 71%, 36%, and 25% for incomplete clinical responders undergoing surgery on the primary tumour who did not undergo treatment for metastatic disease.
CONCLUSION Metastatic oesophageal cancer represents a unique challenge, but aggressive treatment can be rewarded with impressive survival data. In view of recent advances in targeted therapies, intensive follow-up may yield a greater number of patients with curative potential and thus improved long-term survival.
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Affiliation(s)
- Lianne Pickett
- Department of Surgery, Connolly Hospital, Blanchardstown, Dublin D15 X40D, Ireland
| | - Mary Dunne
- Clinical Trials Resource Unit, St Luke's Radiation Oncology Network, Dublin D06 HH36, Ireland
| | - Orla Monaghan
- Department of Radiation Oncology, St Luke's Radiation Oncology Network, Dublin D06 HH36, Ireland
| | - Liam Grogan
- Department of Medical Oncology, Beaumont Hospital, Dublin D09 V2N0, Ireland
| | - Oscar Breathnach
- Department of Medical Oncology, Beaumont Hospital, Dublin D09 V2N0, Ireland
| | - Thomas N Walsh
- Department of Surgery, RCSI Bahrain, Adliya 15503, Bahrain
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Early myelostimulation in patients with locally advanced gastric cancer after fluorouracil plus platinum-based neoadjuvant chemotherapy is related to poor prognosis. Cancer Chemother Pharmacol 2021; 87:701-710. [PMID: 33611625 DOI: 10.1007/s00280-021-04243-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2020] [Accepted: 02/05/2021] [Indexed: 12/23/2022]
Abstract
PURPOSE Some cancer patients experience an increase in the leukocyte count, platelet count, and absolute neutrophil count compared to the baseline level after chemotherapy. We identify this phenomenon as "myelostimulation", which seems to go against the myelosuppression properties of chemotherapy drugs. However, the clinical value of "myelostimulation" that appears early after fluorouracil plus platinum-based neoadjuvant chemotherapy (NACT) in patients with locally advanced gastric cancer (LAGC) remains unclear. METHOD Patients with LAGC who underwent fluorouracil plus platinum-based NACT and radical resection from January 2010 to January 2015 were included. Patients were divided into an increased group and a decreased group based on the leukocyte count, platelet count, and absolute neutrophil count in the early stage after NACT, compared with the baseline blood routine examination results. The prognosis was compared between the increased group and the decreased group. RESULTS The 3-year PFS and 5-year OS of the group with increased leukocyte count, platelet count, and absolute neutrophil count were significantly lower compared to those of the decreased group. Based on the multivariate analysis, increased absolute neutrophil count is an independent risk factor for 3-year PFS (P < 0.001, HR 3.003, 95% CI 1.639-5.495) and 5-year OS (P = 0.003, HR 2.611, 95% CI 1.374-4.950), and increased platelet count is an independent risk factor for 5-year OS (P = 0.037, HR 2.033, 95% CI 1.044-3.953). CONCLUSION The "myelostimulation" that occurs in patients with LAGC in the early stage (3-5 days) after fluorouracil plus platinum-based NACT is related to a poor prognosis, which is a simple and effective method to screen related patients with unfavored outcomes. Notably, the increase in absolute neutrophil count and platelet count has been proved to be an independent risk factor.
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Seth A, Derami HG, Gupta P, Wang Z, Rathi P, Gupta R, Cao T, Morrissey JJ, Singamaneni S. Polydopamine-Mesoporous Silica Core-Shell Nanoparticles for Combined Photothermal Immunotherapy. ACS APPLIED MATERIALS & INTERFACES 2020; 12:42499-42510. [PMID: 32838525 PMCID: PMC7942218 DOI: 10.1021/acsami.0c10781] [Citation(s) in RCA: 55] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/04/2023]
Abstract
Cancer immunotherapy involves a cascade of events that ultimately leads to cytotoxic immune cells effectively identifying and destroying cancer cells. Responsive nanomaterials, which enable spatiotemporal orchestration of various immunological events for mounting a highly potent and long-lasting antitumor immune response, are an attractive platform to overcome challenges associated with existing cancer immunotherapies. Here, we report a multifunctional near-infrared (NIR)-responsive core-shell nanoparticle, which enables (i) photothermal ablation of cancer cells for generating tumor-associated antigen (TAA) and (ii) triggered release of an immunomodulatory drug (gardiquimod) for starting a series of immunological events. The core of these nanostructures is composed of a polydopamine nanoparticle, which serves as a photothermal agent, and the shell is made of mesoporous silica, which serves as a drug carrier. We employed a phase-change material as a gatekeeper to achieve concurrent release of both TAA and adjuvant, thus efficiently activating the antigen-presenting cells. Photothermal immunotherapy enabled by these nanostructures resulted in regression of primary tumor and significantly improved inhibition of secondary tumor in a mouse melanoma model. These biocompatible, biodegradable, and NIR-responsive core-shell nanostructures simultaneously deliver payload and cause photothermal ablation of the cancer cells. Our results demonstrate potential of responsive nanomaterials in generating highly synergistic photothermal immunotherapeutic response.
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Affiliation(s)
- Anushree Seth
- Department of Mechanical Engineering and Materials Science, Institute of Materials Science and Engineering, Washington University in St. Louis, Saint Louis, MO 63130, USA
| | - Hamed Gholami Derami
- Department of Mechanical Engineering and Materials Science, Institute of Materials Science and Engineering, Washington University in St. Louis, Saint Louis, MO 63130, USA
| | - Prashant Gupta
- Department of Mechanical Engineering and Materials Science, Institute of Materials Science and Engineering, Washington University in St. Louis, Saint Louis, MO 63130, USA
| | - Zheyu Wang
- Department of Mechanical Engineering and Materials Science, Institute of Materials Science and Engineering, Washington University in St. Louis, Saint Louis, MO 63130, USA
| | - Priya Rathi
- Department of Chemistry, Washington University in St. Louis, Saint Louis, MO 63130, USA
| | - Rohit Gupta
- Department of Mechanical Engineering and Materials Science, Institute of Materials Science and Engineering, Washington University in St. Louis, Saint Louis, MO 63130, USA
| | - Thao Cao
- Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO 63130, USA
| | - Jeremiah J. Morrissey
- Department of Anesthesiology, Siteman Cancer Center, Washington University in St. Louis, St. Louis, MO, 63110, USA
| | - Srikanth Singamaneni
- Department of Mechanical Engineering and Materials Science, Institute of Materials Science and Engineering, Washington University in St. Louis, Saint Louis, MO 63130, USA
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The significance of scirrhous gastric cancer cell lines: the molecular characterization using cell lines and mouse models. Hum Cell 2018; 31:271-281. [PMID: 29876827 DOI: 10.1007/s13577-018-0211-4] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2018] [Accepted: 05/10/2018] [Indexed: 12/12/2022]
Abstract
Scirrhous gastric cancer (SGC) exhibits aggressiveness of the rapid infiltrating tumor cells with abundant fibroblasts. Experimental studies using SGC cell lines have obtained useful information about this cancer. Our literature search divulged a total of 18 SGC cell lines; two cell lines were established from primary SGC and the other lines were established from a metastatic lesion of SGC. Fibroblast growth factor receptor 2 (FGFR2) and transforming growth factor-beta receptor (TβR) are linked to the rapid development of SGC. Cross-talk between the cancer cells and cancer-associated fibroblasts (CAFs) has been shown to contribute to the progression of SGC. Chemokine (C-X-C motif) receptor 1 (CXCR1) from SGC cells might be associated with the abundant CAFs in cancer microenvironments. The in vivo models established using SGC cell lines are expected to serve as a useful tool for the development of drugs such as FGFR2 inhibitors, TβR inhibitors, and CXCR1 inhibitors, which might be promising as SGC treatments. However, the number of available SGC cell lines is insufficient for the clarification of the entire biologic behavior of SGC. Since the mechanisms responsible for the characteristic aggressiveness of SGC are not fully elucidated, the establishment of new SGC cell lines could help clarify the biological behavior of SGC and contribute to its treatment.
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Jiménez-González M, Plaza-García S, Arizeta J, Bianchessi S, Trigueros C, Reese T. A longitudinal MRI study on lymph nodes histiocytosis of a xenograft cancer model. PLoS One 2017; 12:e0181043. [PMID: 28704462 PMCID: PMC5509248 DOI: 10.1371/journal.pone.0181043] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2015] [Accepted: 06/26/2017] [Indexed: 01/22/2023] Open
Abstract
BACKGROUND Efforts are continuously made to detect and investigate the pivotal processes and interplay between the response of sentinel lymph node and malignant cells from a primary tumor. Conversely, some frequently used tumor animal models, such as human cancer xenografts, rarely feature metastasis. Therefore, lymph node alterations are seldom assessed. We consider that studying lymph node response could contribute to the understanding of host reaction to cancer. In the present study, we explored the presence of regional lymph node alterations in parallel with tumor growth using a pancreatic tumor xenograft model which does not develop metastasis. METHODS AND FINDINGS We established an animal cancer model by the subcutaneous inoculation of PANC-1 (a metastatic human pancreatic cancer cell line) in the left upper flank of athymic nude mice. Tumor animals, along with controls (n = 7 / group) were subjected to Magnetic Resonance Imaging (MRI) in order to follow tumor growth and brachial and axillary lymph nodes alterations over several weeks. Further histological analyses were performed at the end of the study. The individual average of the different lymph nodes sizes was 15-40% larger in the tumor animals compared to control animals at week 8 to week 20. The tumor size and lymph node size were not correlated. Histological analysis of the lymph nodes showed paracortical histiocytosis. No metastasis to lymph nodes could be detected by histology. In tumor bearing animals, histiocytosis was associated with isolated apoptotic bodies and migration of human tumoral cells was confirmed by specific immunostaining of human origin markers. CONCLUSIONS The lack of metastasis as well as the pathological manifestation of the lymph node alteration in this pre-clinical model established here parallels findings in patients with sinus histiocytosis that is correlated with improved survival.
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Affiliation(s)
- María Jiménez-González
- Magnetic Resonance Imaging Group, CIC biomaGUNE, San Sebastián, Guipúzcoa, Spain
- Metabolism Division, Johns Hopkins University, Baltimore, Maryland, United States of America
| | - Sandra Plaza-García
- Magnetic Resonance Imaging Group, CIC biomaGUNE, San Sebastián, Guipúzcoa, Spain
| | - Janire Arizeta
- Fundación Inbiomed, Hematopoietic and Mesenchymal Stem Cell lab, Guipúzcoa, Spain
| | - Silvia Bianchessi
- Mouse & Animal Pathology lab (MAPLab) Filarete foundation, Milano, Italy
| | - César Trigueros
- Fundación Inbiomed, Hematopoietic and Mesenchymal Stem Cell lab, Guipúzcoa, Spain
| | - Torsten Reese
- Magnetic Resonance Imaging Group, CIC biomaGUNE, San Sebastián, Guipúzcoa, Spain
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Kodera Y. Neoadjuvant chemotherapy for gastric adenocarcinoma in Japan. Surg Today 2017; 47:899-907. [PMID: 28247105 DOI: 10.1007/s00595-017-1473-2] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2016] [Accepted: 12/21/2016] [Indexed: 12/23/2022]
Abstract
Surgery had been and remains a mainstay in the treatment of gastric cancer. The Japanese surgical oncologists employed surgery-first approach to treat gastric cancer because of the widespread use of D2 lymph node dissection and the high incidence of oncologically resectable cancer, and early attempts at the multimodality treatment strategy featured surgery followed by postoperative chemotherapy. Although evidence to treat Stage II/III gastric cancer with this strategy is now abundant in the Far East, poor compliance of the post-gastrectomy patients to intense combination chemotherapies has been a limitation associated with this strategy. Evidence in support of neoadjuvant chemotherapy in the West and in various other types of cancer prompted the Japan Clinical Oncology Group (JCOG) researchers to explore this strategy, primarily for a selected population of locally advanced cancer that could either be unresectable by the surgery-first approach or is known to suffer from a poor prognosis; cancers with bulky lymph node metastases or those with a scirrhous phenotype. Encouraged by some promising results from these neoadjuvant trials and taking into account the aforementioned limitations associated with postoperative chemotherapy, the JCOG researchers decided to embark on a phase III trial to explore neoadjuvant chemotherapy among patients with clinically Stage III cancer. This review describes the development of the neoadjuvant strategy for gastric cancer in Japan, mainly by going through a series of clinical trials conducted by the JCOG.
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Affiliation(s)
- Yasuhiro Kodera
- Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, 65, Tsurumai-cho, Showa-ku, Nagoya, Aichi, 466-8550, Japan.
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Heeg S, Das KK, Reichert M, Bakir B, Takano S, Caspers J, Aiello NM, Wu K, Neesse A, Maitra A, Iacobuzio-Donahue CA, Hicks P, Rustgi AK. ETS-Transcription Factor ETV1 Regulates Stromal Expansion and Metastasis in Pancreatic Cancer. Gastroenterology 2016; 151:540-553.e14. [PMID: 27318148 PMCID: PMC5002361 DOI: 10.1053/j.gastro.2016.06.005] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2015] [Revised: 05/13/2016] [Accepted: 06/06/2016] [Indexed: 12/18/2022]
Abstract
BACKGROUND & AIMS The ETS-transcription factor ETV1 is involved in epithelial-mesenchymal transition during pancreatic development and is induced in mouse pancreatic intraepithelial neoplasia (PanIN) and pancreatic ductal adenocarcinoma (PDAC). We investigated the function of ETV1 in stromal expansion of PDAC and metastasis, as well as its effects on a novel downstream target Sparc, which encodes a matricellular protein found in PDAC stroma that has been associated with invasiveness, metastasis and poor patient outcomes. METHODS Pancreatic ductal cells were isolated from Pdx1Cre;Kras(G12D/+) mice (PanIN), Pdx1Cre;Kras(G12D/+);p53(fl/+) and Pdx1Cre;Kras(G12D/+);p53(fl/+);Rosa26(YFP) mice (PDAC), and Pdx1Cre;Kras(G12D/+);p53(fl/+);Sparc(-/-) mice. Cells were grown in 3-dimensional organoid culture to analyze morphology, proliferation, and invasion. Human PanIN and PDAC tissues were evaluated for ETV1 expression. Orthotopic pancreatic transplants of ETV1-overexpressing PDAC and respective control cells were performed. RESULTS ETV1 expression was significantly increased in human PanINs and, even more so, in primary and metastatic PDAC. Analyses of mouse orthotopic xenografts revealed that ETV1 induced significantly larger primary tumors than controls, with significantly increased stromal expansion, ascites and metastases. In 3-dimensional organoids, ETV1 disrupted cyst architecture, induced EMT, and increased invasive capacity. Furthermore, we identified Sparc as a novel functional gene target of Etv1 by luciferase assays, and SPARC and ETV1 proteins co-localized in vivo. Disruption of Sparc abrogates the phenotype of stromal expansion and metastasis found with ETV1 overexpression in vivo. We identified hyaluronan synthase 2 (Has2) as another novel downstream factor of Etv1; that may mediate ETV1's significant expansion of hyaluronic acid in PDAC stroma. Conversely, disruption of Etv1 in PDAC mice (Pdx1Cre;Kras(G12D/+);p53(fl/+);Rosa26(YFP);Cre;Etv1(fl/fl)) reduced levels of SPARC and hyaluronic acid in the stroma. CONCLUSIONS ETV1 is critical in the desmoplastic stromal expansion and metastatic progression of pancreatic cancer in mice, mediated functionally in part through Sparc and Has2.
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Affiliation(s)
- Steffen Heeg
- Division of Gastroenterology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Department of Medicine II, Medical Center, University of Freiburg; Freiburg, Germany
| | - Koushik K Das
- Division of Gastroenterology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Maximilian Reichert
- Division of Gastroenterology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; II. Medizinische Klinik, Technical University of Munich, Munich, Germany
| | - Basil Bakir
- Division of Gastroenterology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Shigetsugu Takano
- Division of Gastroenterology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Julia Caspers
- Department of Medicine II, Medical Center, University of Freiburg; Freiburg, Germany
| | - Nicole M Aiello
- Division of Gastroenterology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Katherine Wu
- Division of Gastroenterology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Albrecht Neesse
- Division of Gastroenterology and Gastrointestinal Oncology, University Medical Centre Goettingen, Goettingen, Germany
| | - Anirban Maitra
- University of Texas, MD Anderson Cancer Center, Houston, Texas
| | - Christine A Iacobuzio-Donahue
- David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Philip Hicks
- Division of Gastroenterology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Anil K Rustgi
- Division of Gastroenterology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
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Park JY, Kook MC, Eom BW, Yoon HM, Kim SJ, Rho JY, Kim SK, Kim YI, Cho SJ, Lee JY, Kim CG, Choi IJ, Kim YW, Ryu KW. Practical intraoperative pathologic evaluation of sentinel lymph nodes during sentinel node navigation surgery in gastric cancer patients - Proposal of the pathologic protocol for the upcoming SENORITA trial. Surg Oncol 2016; 25:139-46. [PMID: 27566014 DOI: 10.1016/j.suronc.2016.05.004] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2016] [Accepted: 05/08/2016] [Indexed: 02/07/2023]
Abstract
Over the last decade, as the number of patients with early gastric cancer increased and the subsequent survival rate improved, there has been a consistent effort to verify the applicability of the sentinel node concept in gastric cancer in a bid to improve postoperative quality of life in these patients. During sentinel node navigation surgery in gastric cancer patients, intraoperative pathologic examination of the retrieved sentinel nodes plays a critical role in determining the extent of surgery, but the optimal method is still under debate. Currently, a multicenter, phase III clinical trial is underway to compare laparoscopic sentinel basin dissection with stomach preserving surgery and standard laparoscopic gastrectomy in terms of oncologic outcomes in patients with clinical stage T1N0 gastric cancer. Herein, the currently available intraoperative pathologic techniques are reviewed and their clinical significance and applicability are appraised based on the published literature. The proper pathologic examination of the sentinel lymph nodes in an upcoming clinical trial (SENORITA trial) is also proposed here based on this review.
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Affiliation(s)
- Ji Yeon Park
- Department of Surgery, Research Institute and Hospital, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang, Gyeonggi-do, 10408, Republic of Korea
| | - Myeong-Cherl Kook
- Center for Gastric Cancer, Research Institute and Hospital, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang, Gyeonggi-do, 10408, Republic of Korea.
| | - Bang Wool Eom
- Center for Gastric Cancer, Research Institute and Hospital, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang, Gyeonggi-do, 10408, Republic of Korea
| | - Hong Man Yoon
- Center for Gastric Cancer, Research Institute and Hospital, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang, Gyeonggi-do, 10408, Republic of Korea
| | - Soo Jin Kim
- Center for Gastric Cancer, Research Institute and Hospital, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang, Gyeonggi-do, 10408, Republic of Korea
| | - Ji Yoon Rho
- Center for Gastric Cancer, Research Institute and Hospital, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang, Gyeonggi-do, 10408, Republic of Korea
| | - Seok-Ki Kim
- Department of Nuclear Medicine, Research Institute and Hospital, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang, Gyeonggi-do, 10408, Republic of Korea
| | - Young-Il Kim
- Center for Gastric Cancer, Research Institute and Hospital, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang, Gyeonggi-do, 10408, Republic of Korea
| | - Soo-Jeong Cho
- Center for Gastric Cancer, Research Institute and Hospital, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang, Gyeonggi-do, 10408, Republic of Korea
| | - Jong Yeul Lee
- Center for Gastric Cancer, Research Institute and Hospital, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang, Gyeonggi-do, 10408, Republic of Korea
| | - Chan Gyoo Kim
- Center for Gastric Cancer, Research Institute and Hospital, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang, Gyeonggi-do, 10408, Republic of Korea
| | - Il Ju Choi
- Center for Gastric Cancer, Research Institute and Hospital, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang, Gyeonggi-do, 10408, Republic of Korea
| | - Young-Woo Kim
- Department of Cancer Control and Policy, Graduate School of Cancer Science & Policy, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang, Gyeonggi-do, 10408, Republic of Korea
| | - Keun Won Ryu
- Center for Gastric Cancer, Research Institute and Hospital, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang, Gyeonggi-do, 10408, Republic of Korea
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Kakiuchi T, Takahara T, Kasugai Y, Arita K, Yoshida N, Karube K, Suguro M, Matsuo K, Nakanishi H, Kiyono T, Nakamura S, Osada H, Sekido Y, Seto M, Tsuzuki S. Modeling mesothelioma utilizing human mesothelial cells reveals involvement of phospholipase-C beta 4 in YAP-active mesothelioma cell proliferation. Carcinogenesis 2016; 37:1098-1109. [PMID: 27559111 DOI: 10.1093/carcin/bgw084] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2016] [Revised: 07/13/2016] [Accepted: 08/06/2016] [Indexed: 12/17/2022] Open
Abstract
Mesotheliomas are frequently characterized by disruption of Hippo pathway due to deletion and/or mutation in genes, such as neurofibromin 2 ( NF2 ). Hippo disruption attenuates yes-associated protein (YAP) phosphorylation allowing YAP to translocate to the nucleus and regulate gene expression. The role of disrupted Hippo pathway in maintenance of established mesotheliomas has been extensively investigated using cell lines; however, its involvement in development of human mesothelioma has not been explored much. Here, we employed immortalized human mesothelial cells to disrupt Hippo pathway. YAP phosphorylation was reduced on NF2 knockdown and the cells exhibited altered growth in vitro , developing tumors when transplanted into nude mice. Similar results were obtained from enforced expression of wild-type or constitutively active (S127A) YAP, indicating the crucial role of activated YAP in the transformation of mesothelial cells. Gene expression analysis comparing control- and YAP-transduced immortalized human mesothelial cells revealed phospholipase-C beta 4 ( PLCB4 ) to be among the genes highly upregulated by YAP. PLCB4 was upregulated by YAP in immortalized human mesothelial cells and downregulated on YAP knockdown in Hippo-disrupted mesothelioma cell lines. PLCB4 knockdown attenuated the growth of YAP-transduced immortalized mesothelial cells and YAP-active, but not YAP-nonactive, mesothelioma cell lines. Our model system thus provides a versatile tool to investigate the mechanisms underlying mesothelioma development. We suggest that PLCB4 may be an attractive drug target for the treatment of mesothelioma.
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Affiliation(s)
- Tatsuo Kakiuchi
- Division of Molecular Medicine, Aichi Cancer Center Research Institute , Nagoya 464-8681 , Japan.,Department of Pathology and Clinical Laboratories, Nagoya University Hospital , Nagoya 466-0065 , Japan
| | - Taishi Takahara
- Division of Molecular Medicine, Aichi Cancer Center Research Institute , Nagoya 464-8681 , Japan.,Department of Pathology and Clinical Laboratories, Nagoya University Hospital , Nagoya 466-0065 , Japan
| | - Yumiko Kasugai
- Division of Molecular Medicine, Aichi Cancer Center Research Institute , Nagoya 464-8681 , Japan
| | - Kotaro Arita
- Third Department of Internal Medicine, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama , Toyama 930-0194 , Japan
| | - Noriaki Yoshida
- Department of Pathology, Kurume University School of Medicine , Kurume 830-0011 , Japan.,Present address: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA
| | - Kennosuke Karube
- Laboratory of Cytopathology, Faculty of Medicine, University of the Ryukyus , Okinawa 903-0215 , Japan
| | - Miyuki Suguro
- Division of Molecular Medicine, Aichi Cancer Center Research Institute , Nagoya 464-8681 , Japan
| | - Keitaro Matsuo
- Division of Molecular Medicine, Aichi Cancer Center Research Institute , Nagoya 464-8681 , Japan
| | - Hayao Nakanishi
- Laboratory of Pathology and Clinical Research, Aichi Cancer Center , Aichi Hospital, Okazaki 444-0011 , Japan
| | - Tohru Kiyono
- Division of Carcinogenesis and Cancer Prevention, National Cancer Center Research Institute , Tokyo 104-0045 , Japan
| | - Shigeo Nakamura
- Department of Pathology and Clinical Laboratories, Nagoya University Hospital , Nagoya 466-0065 , Japan
| | - Hirotaka Osada
- Division of Molecular Oncology, Aichi Cancer Center Research Institute , Nagoya 464-8681 , Japan.,Department of Cancer Genetics, Program in Function Construction Medicine, Nagoya University Graduate School of Medicine , Nagoya 466-8550 , Japan and
| | - Yoshitaka Sekido
- Division of Molecular Oncology, Aichi Cancer Center Research Institute , Nagoya 464-8681 , Japan.,Department of Cancer Genetics, Program in Function Construction Medicine, Nagoya University Graduate School of Medicine , Nagoya 466-8550 , Japan and
| | - Masao Seto
- Department of Pathology, Kurume University School of Medicine , Kurume 830-0011 , Japan
| | - Shinobu Tsuzuki
- Division of Molecular Medicine, Aichi Cancer Center Research Institute , Nagoya 464-8681 , Japan.,Department of Biochemistry, Aichi Medical University School of Medicine , Nagakute, Aichi 480-1195 , Japan
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Chandrasekaran S, Chan MF, Li J, King MR. Super natural killer cells that target metastases in the tumor draining lymph nodes. Biomaterials 2015; 77:66-76. [PMID: 26584347 DOI: 10.1016/j.biomaterials.2015.11.001] [Citation(s) in RCA: 59] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2015] [Revised: 10/29/2015] [Accepted: 11/01/2015] [Indexed: 11/27/2022]
Abstract
Tumor draining lymph nodes are the first site of metastasis in most types of cancer. The extent of metastasis in the lymph nodes is often used in staging cancer progression. We previously showed that nanoscale TRAIL liposomes conjugated to human natural killer cells enhance their endogenous therapeutic potential in killing cancer cells cultured in engineered lymph node microenvironments. In this work, it is shown that liposomes decorated with apoptosis-inducing ligand TRAIL and an antibody against a mouse natural killer cell marker are carried to the tumor draining inguinal lymph nodes and prevent the lymphatic spread of a subcutaneous tumor in mice. It is shown that targeting natural killer cells with TRAIL liposomes enhances their retention time within the tumor draining lymph nodes to induce apoptosis in cancer cells. It is concluded that this approach can be used to kill cancer cells within the tumor draining lymph nodes to prevent the lymphatic spread of cancer.
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Affiliation(s)
| | - Maxine F Chan
- Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY, USA
| | - Jiahe Li
- Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY, USA
| | - Michael R King
- Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY, USA.
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11
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He H, Shen Z, Wang X, Qin J, Sun Y, Qin X. Survival benefit of greater number of lymph nodes dissection for advanced node-negative gastric cancer patients following radical gastrectomy. Jpn J Clin Oncol 2015; 46:63-70. [DOI: 10.1093/jjco/hyv159] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2015] [Accepted: 09/29/2015] [Indexed: 12/20/2022] Open
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12
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Tavares A, Monteiro-Soares M, Viveiros F, Maciel Barbosa J, Dinis-Ribeiro M. Occult Tumor Cells in Lymph Nodes of Patients with Gastric Cancer: A Systematic Review on Their Prevalence and Predictive Role. Oncology 2015; 89:245-54. [PMID: 26160338 DOI: 10.1159/000433543] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2014] [Accepted: 05/18/2015] [Indexed: 09/29/2023]
Abstract
BACKGROUND AND AIMS The presence of lymph node (LN) metastasis is a key prognostic factor for gastric adenocarcinoma. However, even among patients without LN metastasis (N0), recurrence may occur. In some of these cases, occult tumor cells (OTC) are thought to play an important role. We aimed to determine the prevalence of OTC and its clinical relevance. METHODS We conducted a systematic review of studies in English published until September 2013 that addressed OTC prevalence and/or its clinical relevance. The studies were retrieved from the MEDLINE database. RESULTS We included 42 studies. The most frequently used methods for detecting OTC were immunohistochemical examination (IHC) and/or polymerase chain reaction (PCR) with a wide range of markers. Using IHC for OTC detection, in patients and in LN, the prevalence varied from 9 to 88% and 0.4 to 42%, respectively. With PCR, it ranged from 17 to 46% in patients, and from 3 to 33% in LN. In the studies assessing the predictive role of OTC in gastric cancer recurrence (n=24), 8 studies found no statistical association, while 18 concluded that OTC presence was associated with poorer prognosis. However, only 6 studies presented a significantly different 5-year survival rate between patients with and without LN micrometastasis. CONCLUSIONS OTC seems to occur in gastric cancer patients with a variable prevalence, depending on the definition, methods and setting. The majority of the retrieved studies (75%) evaluating the predictive role of OTC conclude that its presence is associated with a worse prognosis.
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Affiliation(s)
- Amelia Tavares
- General Surgery Department, Centro Hospitalar de Vila Nova de Gaia/Espinho, Vila Nova de Gaia, Portugal
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Yamada E, Ishii G, Aramaki N, Aokage K, Hishida T, Yoshida J, Kojima M, Nagai K, Ochiai A. Tumor-size-based morphological features of metastatic lymph node tumors from primary lung adenocarcinoma. Pathol Int 2014; 64:591-600. [PMID: 25354789 DOI: 10.1111/pin.12213] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2014] [Accepted: 09/11/2014] [Indexed: 01/06/2023]
Abstract
Most primary lung adenocarcinomas show histological diversity, however, histological diversity in the metastatic lymph node tumors (LNT) is not well defined. The aim of this study was to explore the histological characteristics of the metastatic LNT based on their sizes. We analyzed 163 primary tumors and 509 metastatic LNTs. When the primary tumor showed papillary-predominant subtype, the most frequent histological subtype in the metastatic LNT that were ≤2 mm in diameter was solid subtype (49%), followed by papillary subtype (35%); on the other hand, in the metastatic LNT measuring >2 mm in size, the frequency of tumors showing papillary-predominant subtype increased significantly to 52% (P = 0.04). When the primary tumor showed acinar-predominant subtype, the most predominant subtype in the ≤2 mm metastatic LN tumors was acinar subtype (55%), followed by solid subtype (40%), with the frequency of acinar subtype increasing significantly to 76% in the metastatic LNT that were >2 mm in diameter (P = 0.04). These results indicate that solid subtype is the characteristic histological subtype in the early phase of the LN metastatic process, and that as the metastatic LNT grow larger, they develop morphological features resembling those in the primary tumor.
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Affiliation(s)
- Eiji Yamada
- Division of Pathology, Research Center for Innovative Oncology, National Cancer Center Hospital East, Chiba, Japan; Division of Thoracic Surgery, National Cancer Center Hospital East, Chiba, Japan
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14
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Nakata S, Tanaka H, Ito Y, Hara M, Fujita M, Kondo E, Kanemitsu Y, Yatabe Y, Nakanishi H. Deficient HER3 expression in poorly-differentiated colorectal cancer cells enhances gefitinib sensitivity. Int J Oncol 2014; 45:1583-93. [PMID: 25017791 DOI: 10.3892/ijo.2014.2538] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2014] [Accepted: 05/30/2014] [Indexed: 11/06/2022] Open
Abstract
Poorly-differentiated colorectal cancers (PD-CRC) show high metastatic potential and poor prognosis. However, molecular characteristics of PD-CRC remain unknown to date, particularly in molecular targeting therapy for patients with PD-CRC. In this study, we examined the expression of EGFR, HER2 and HER3 in PD-CRC by immunohistochemical analysis of archived clinical specimens of primary tumors and investigated the sensitivity of PD-CRC cell lines to gefitinib, a tyrosine kinase inhibitor for EGFR in vitro. We found that HER3 expression of PD-CRC among members of the HER family was significantly lower than that of well to moderately differentiated CRC (WMD-CRC) and 37% of the PD cases showed a EGFR+/HER2+/HER3- expression pattern. COLM-5 cells, a PD-CRC-derived cell line, which exhibits EGFR+/HER2+/HER3- expression pattern and recapitulates the typical histology of PD-CRC in xenografted tumors, showed high gefitinib sensitivity both in vitro and in vivo, compared with WMD-CRC cell line (COLM-2). Treatment with gefitinib resulted in the upregulation of p27Kip1 expression and induction of G1 cell cycle arrest, concomitantly associated with inactivation of PI3K/Akt signaling in COLM-5 cells and marked inhibition of xenografted tumors in nude mice, but not evident in COLM-2 cells. Treatment with sodium butyrate, an HDAC inhibitor that induces differentiation, upregulated the expression of HER3 associated with enhancement of the PI3K/Akt signaling, attenuated gefitinib-mediated p27Kip1 upregulation and reduced gefitinib sensitivity in COLM-5 cells in vitro. Furthermore, enforced expression of HER3 in COLM-5 cells resulted in significant resistance to gefitinib treatment both in vitro and in vivo. These findings suggest that deficient HER3 expression plays an important role in gefitinib sensitivity and that a malignant subset of PD with EGFR+/HER2+/HER3- phenotype is a potential candidate for a target of anti-EGFR molecular therapy such as gefitinib.
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Affiliation(s)
- Susumu Nakata
- Division of Oncological Pathology, Aichi Cancer Center Research Institute, Nagoya 464-8681, Japan
| | - Harunari Tanaka
- Division of Oncological Pathology, Aichi Cancer Center Research Institute, Nagoya 464-8681, Japan
| | - Yuichi Ito
- Department of Gastroenterological Surgery, Aichi Cancer Center Central Hospital, Nagoya 464-8681, Japan
| | - Masayasu Hara
- Department of Gastroenterological Surgery, Nagoya City University, Nagoya 464-8681, Japan
| | - Mitsugu Fujita
- Department of Microbiology, Kinki University, Graduate School of Medical Sciences, Osaka 589-8511, Japan
| | - Eisaku Kondo
- Division of Oncological Pathology, Aichi Cancer Center Research Institute, Nagoya 464-8681, Japan
| | - Yukihide Kanemitsu
- Colorectal Surgery Division, National Cancer Center Hospital, Tokyo 104-0045, Japan
| | - Yasushi Yatabe
- Department of Pathology and Molecular Medicine, Aichi Cancer Center Central Hospital, Nagoya 464-8681, Japan
| | - Hayao Nakanishi
- Laboratory of Pathology and Clinical Research, Aichi Cancer Center Aichi Hospital, Okazaki 444-0011, Japan
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15
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Huang X, Li Y, Zhang J, Xu Y, Tian Y, Ma K. Ganglioside GM3 inhibits hepatoma cell motility via down-regulating activity of EGFR and PI3K/AKT signaling pathway. J Cell Biochem 2013; 114:1616-24. [PMID: 23355442 DOI: 10.1002/jcb.24503] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2012] [Accepted: 01/10/2013] [Indexed: 02/03/2023]
Abstract
Two related sublines derived from murine ascites hepatoma cell lines Hca-F25, which were selected for their markedly different metastatic potential to lymph nodes, were found to be distinct in their ganglioside patterns. The low metastatic cell line (HcaP) contained a major ganglioside GM3, whereas the high metastatic cell line (HcaF) contained a major ganglioside GM2. Suppression of GM3 by P4 enhanced the mobility and migration of the low metastatic HcaP cells in vitro. Increase in GM3 content in high metastatic HcaF cells by addition of exogenous GM3 inhibited the mobility and migration. These results suggested that the differences in lymphatic metastasis potential between these two cell lines could be attributed to the differences in their ganglioside compositions, and GM3 could suppress the motility and migration of these cells. Further, we investigated the mechanism by which GM3 suppressed the cell mobility and migration. The results showed that suppression of GM3 synthesis by P4 in low metastatic HcaP cells promoted PKB/Akt phosphorylation at Ser473 and Thr308, and phosphorylation of EGFR at the Tyr1173. In contrast, increase in GM3 content in high metastatic HcaF cells by addition of exogenous GM3 into the culture medium suppressed phosphorylation of PKB/Akt and EGFR at the same residues. Taken together, these results suggested that the mechanism of GM3-suppressed cell motility and migration may involve the inhibition of phosphorylation of EGFR and the activity of PI3K/AKT signaling pathway.
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Affiliation(s)
- X Huang
- Department of Biochemistry and Molecular Biology, Dalian Medical University, Dalian 116044, China; Department of Clinical Biochemistry, College of Laboratory Medicine, Dalian Medical University, Dalian 116044, China
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Kim DH, Kim SM, Hyun JK, Choi MG, Noh JH, Sohn TS, Bae JM, Kim S. Changes in postoperative recurrence and prognostic risk factors for patients with gastric cancer who underwent curative gastric resection during different time periods. Ann Surg Oncol 2013; 20:2317-27. [PMID: 23677605 DOI: 10.1245/s10434-012-2700-0] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2012] [Indexed: 12/18/2022]
Abstract
BACKGROUND Current rates of survival for gastric cancer patients are much improved compared with those of the past. The purpose of our study was to analyze the survival of gastric cancer patients according to time period and to examine how different prognostic factors are related to changing survival rates. METHODS We analyzed data from 7,757 patients who underwent curative gastrectomy after diagnoses of gastric cancer at Samsung Medical Center from 1994 to 2006. Clinicopathologic characteristics and prognostic factors were analyzed retrospectively, with patients divided into period I, from 1994 to 2001, and period II, from 2002 to 2006. RESULTS The 5-year, disease-free survival rate of patients with gastric cancer increased significantly from 76.7 % during period I to 85.9 % during period II (p < 0.001). The prognosis of the patient who underwent surgery during period I was worse than that of the patient in period II. When multivariate analyses were performed for each time period, independent prognostic factors for period I included patient age >60 years, tumor located in the whole stomach, tumor size, stage, vascular invasion, perineural invasion, and adjuvant chemotherapy. For period II, tumor size, vascular, and adjuvant chemotherapy were no longer independent prognostic risk factors. CONCLUSIONS The disease-free survival of gastric cancer improved and prognostic factors changed over time. Active, concurrent chemoradiotherapy together with radical gastric resection performed by an expert surgeon seemed to contribute to the improvement in the survival rates of gastric cancer.
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Affiliation(s)
- Dae Hoon Kim
- Department of Surgery, Chungbuk National University Hospital, Cheongju, Korea.
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Nakanishi H, Ito S, Matsui M, Ito Y, Misawa K, Kodera Y. Noninvasive and real-time fluorescence imaging of peritoneal metastasis in nude mice. Methods Mol Biol 2012; 872:85-95. [PMID: 22700405 DOI: 10.1007/978-1-61779-797-2_6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/12/2023]
Abstract
Peritoneal metastasis is the most important prognostic factor for gastric and ovarian cancer patients. The protocol in this chapter presents in vivo imaging procedures capable of examining the development of peritoneal metastasis from the micrometastasis stage to the advanced stage. We also describe in vivo imaging procedures for monitoring of antimetastatic agents in nude mice. In vivo imaging systems described consist of green fluorescent protein (GFP) or red fluorescent protein (DsRed) gene-tagged metastatic cancer cell lines and a handy detection device for GFP (or DsRed). This system allows both external, noninvasive, and real-time monitoring of the therapeutic effects of drugs within the animal facility and internal visualization of micrometastases at the cellular level using fluorescence microscopy. Selection of micrometastasis-positive mice and timing of drug administration after injection of tumor cells is critical for accurate evaluation of anti-metastatic efficacy. The present real-time fluorescence imaging system using GFP- and DsRed-tagged metastasis models makes it possible to overcome these problems and therefore is an indispensable tool for preclinical metastasis research and drug discovery.
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Affiliation(s)
- Hayao Nakanishi
- Division of Oncological Pathology, Aichi Cancer Center Research Institute, Nagoya, Japan.
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18
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Ozaki H, Matsuzaki H, Ando H, Kaji H, Nakanishi H, Ikehara Y, Narimatsu H. Enhancement of metastatic ability by ectopic expression of ST6GalNAcI on a gastric cancer cell line in a mouse model. Clin Exp Metastasis 2012; 29:229-38. [PMID: 22228572 PMCID: PMC3275730 DOI: 10.1007/s10585-011-9445-1] [Citation(s) in RCA: 56] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2011] [Accepted: 12/09/2011] [Indexed: 11/25/2022]
Abstract
ST6GalNAcI is a sialyltransferase responsible for the synthesis of sialyl Tn (sTn) antigen which is expressed in a variety of adenocarcinomas including gastric cancer especially in advanced cases, but the roles of ST6GalNAcI and sTn in cancer progression are largely unknown. We generated sTn-expressing human gastric cancer cells by ectopic expression of ST6GalNAcI to evaluate metastatic ability of these cells and prognostic effect of ST6GalNAcI and sTn in a mouse model, and identified sTn carrier proteins to gain insight into the function of ST6GalNAcI and sTn in gastric cancer progression. A green fluorescent protein-tagged human gastric cancer cell line was transfected with ST6GalNAcI to produce sTn-expressing cells, which were transplanted into nude mice. STn-positive gastric cancer cells showed higher intraperitoneal metastatic ability in comparison with sTn-negative control, resulting in shortened survival time of the mice, which was mitigated by anti-sTn antibody administration. Then, sTn-carrying proteins were immunoprecipitated from culture supernatants and lysates of these cells, and identified MUC1 and CD44 as major sTn carriers. It was confirmed that MUC1 carries sTn also in human advanced gastric cancer tissues. Identification of sTn carrier proteins will help understand mechanisms of metastatic phenotype acquisition of gastric cancer cells by ST6GalNAcI and sTn.
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Affiliation(s)
- Hidenori Ozaki
- Molecular Medicine Team, Research Center for Medical Glycoscience, National Institute of Advanced Industrial Science and Technology (AIST), Umezono 1-1-1, Tsukuba, Ibaraki 305-8568 Japan
| | - Hideki Matsuzaki
- Lectin Application and Analysis Team, Research Center for Medical Glycoscience, National Institute of Advanced Industrial Science and Technology (AIST), Umezono 1-1-1, Tsukuba, Ibaraki 305-8568 Japan
| | - Hidenobu Ando
- Molecular Medicine Team, Research Center for Medical Glycoscience, National Institute of Advanced Industrial Science and Technology (AIST), Umezono 1-1-1, Tsukuba, Ibaraki 305-8568 Japan
- Glycogene, Inc, Umezono 1-1-1, Tsukuba, Ibaraki 305-8568 Japan
| | - Hiroyuki Kaji
- Glycoproteomics Team, Research Center for Medical Glycoscience, National Institute of Advanced Industrial Science and Technology (AIST), Umezono 1-1-1, Tsukuba, Ibaraki 305-8568 Japan
| | - Hayao Nakanishi
- Division of Oncological Pathology, Aichi Cancer Center Research Institute, Kanokoden 1-1, Chikusa, Nagoya, 464-8681 Japan
| | - Yuzuru Ikehara
- Molecular Medicine Team, Research Center for Medical Glycoscience, National Institute of Advanced Industrial Science and Technology (AIST), Umezono 1-1-1, Tsukuba, Ibaraki 305-8568 Japan
| | - Hisashi Narimatsu
- Glycogene Function Team, Research Center for Medical Glycoscience, National Institute of Advanced Industrial Science and Technology (AIST), Central 2, Umezono 1-1-1, Tsukuba, Ibaraki 305-8568 Japan
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Abstract
The extent of surgical resection for carcinoma of the stomach has been debated for many years. The aims of surgery are to obtain complete histopathological clearance of all possible sites of disease based on oncological principles. This has included radical resection of the primary site with combined organ resection as required and resection of associated lymph nodes. Detailed understanding of the natural history of gastric cancer has resulted in the Pichlmayr total gastrectomy "en principe" approach being super-ceded by a tailored approach according to tumour and patient characteristics. Careful tumour staging is fundamental to the selection of surgical intervention. Endoscopic therapy is recommended for well differentiated, mucosal cancers less than 2 cm in size as the risk of nodal disease is 0-3 %. Recently, these criteria have been extended to include some larger and ulcerated cancers. Although extended lymphadenectomy has formed the basis of radical surgery, Japanese experience has also confirmed that for early gastric cancer involving the submucosa limited nodal resection can achieve the same outcome as standardised D2 lymphadenectomy. The approach to locally advanced T2, T3 and some T4 cancers has been defined by the Japanese rules specifying proximal and distal margins as well as extent of lymph node resection. Translation of Japanese results to Western patients has not been straightforward. Two randomised controlled trials have shown limited or no benefit over conventional limited nodal dissection. However, these studies have not been without criticism and individual specialist practice in the West now preferentially includes D2 lymphadenectomy in suitable patients. Extending conventional D2 lymphadenectomy has been evaluated but the results are not conclusive. Japanese RCTs have not shown an advantage but in selected cases several groups have reported a benefit. Historically, radical gastric surgery in the West was associated with significant morbidity and mortality reflecting the comorbidity of the patient groups. Perioperative approaches have shown that outcome approaching that of radical surgery can be achieved with multimodal therapies for high-risk patient groups for whom radical surgery would be contraindicated. Surgery for gastric cancer needs to be determined by a multidisciplinary team to ensure appropriate procedure selection for an individual patient. This allows all relevant information to be considered and to provide the best chance for high-quality patient outcome.
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Lee HS, Lee HE, Park DJ, Park YS, Kim HH. Precise pathologic examination decreases the false-negative rate of sentinel lymph node biopsy in gastric cancer. Ann Surg Oncol 2011; 19:772-8. [PMID: 21979113 DOI: 10.1245/s10434-011-2106-4] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2010] [Indexed: 12/27/2022]
Abstract
BACKGROUND Gastric cancer has been identified as a target for sentinel lymph node (SLN) navigational surgery. Although accurate evaluation of SLNs is essential for applying the SLN concept to gastric cancer surgery, there is no standardized pathologic examination protocol for SLNs in gastric cancer. METHODS A total of 231 SLNs from 69 patients with cT1-2, N0 gastric cancer were prospectively examined in this study. During the operation, SLNs were sliced at 2-mm intervals, and frozen sections were analyzed by hematoxylin and eosin (HE) staining in 35 patients or HE staining with rapid immunohistochemistry (IHC) for pancytokeratin (CK) in 34 patients. HE staining and CK IHC were performed postoperatively on each remaining SLN. Non-SLNs were evaluated with 2 levels of HE slides and 1 CK IHC. RESULTS Of 35 patients, metastasis was identified in 10 patients by intraoperative HE staining, and in 12 patients by postoperative HE staining and CK IHC. Two patients had isolated tumor cells (ITCs) detectable by postoperative CK IHC; these patients had non-SLN metastasis. We enrolled another 34 patients and examined 147 SLNs by frozen HE and rapid IHC. In this cohort, 26 patients with negative SLNs by intraoperative examination did not have non-SLN metastasis even after deeper sectioning and CK IHC of non-SLNs (sensitivity, 100%; false negative value, 0%). CONCLUSIONS Our study indicated that precise and detailed intraoperative examination decreases the false-negative rate of SLN biopsy. ITCs in SLNs should not be overlooked, and rapid IHC can be helpful for detecting ITCs intraoperatively.
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Affiliation(s)
- Hye Seung Lee
- Department of Pathology, Seoul National University Bundang Hospital, Seongnam, Korea
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Lee HE, Park DJ, Kim WH, Kim HH, Lee HS. High FOXP3+ regulatory T-cell density in the sentinel lymph node is associated with downstream non-sentinel lymph-node metastasis in gastric cancer. Br J Cancer 2011; 105:413-9. [PMID: 21730981 PMCID: PMC3172906 DOI: 10.1038/bjc.2011.248] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
Abstract
Background: We aimed to evaluate the immunologic nature of sentinel lymph nodes (SLNs) in gastric cancer patients and to determine whether it can predict non-SLN metastasis. Methods: Sentinel lymph node samples were collected from 64 gastric carcinoma patients who had undergone gastrectomy with SLN biopsy. One representative SLN sample was selected from each patient and was subjected to immunostaining for CD8, CD57, FOXP3, and DC-LAMP. The numbers of marker-positive cells in each sample were counted. The relationships between various immune cell densities and clinicopathologic parameters or metastasis status of SLNs and non-SLNs were sought. Results: High FOXP3+ Treg density of the SLN was found to be significantly associated with the presence of metastasis in either SLNs or non-SLNs. DC-LAMP+ cell density of the SLN was the highest at the isolated tumours cell level, and this decreased along with an increase in tumour metastasis in either SLNs or non-SLNs. Univariate and multivariate logistic regression models revealed that high FOXP3+ Treg density of the SLN was an independently significant predictor of non-SLN metastasis. Conclusions: This study is the first to indicate an important role of SLNs in metastatic dissemination of gastric cancer. Our findings suggest that Tregs could be a new therapeutic target for regulating the metastasis of gastric cancer.
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Affiliation(s)
- H E Lee
- Department of Pathology, Seoul National University Hospital, 28 Yeongon-dong, Jongno-gu, Seoul 110-744, Korea
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Phase II clinical trial of postoperative S-1 monotherapy for gastric cancer patients with free intraperitoneal cancer cells detected by real-time RT-PCR. World J Surg 2010; 34:2083-9. [PMID: 20379713 DOI: 10.1007/s00268-010-0573-6] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
BACKGROUND We have previously reported the molecular detection of peritoneal micrometastases in patients with gastric cancer by quantifying carcinoembryonic antigen (CEA) mRNA in the peritoneal washes. Patients with CEA mRNA exceeding a cutoff value have a significant risk for developing peritoneal carcinomatosis, but optimal treatment for this population remains unknown. METHODS CEA mRNA (+) patients with gastric cancer were treated postoperatively with S-1 monotherapy. Overall survival, the primary endpoint of this phase II trial, was compared with the historical control, which is comprised of CEA mRNA (+) patients who were not given postoperative chemotherapy. RESULTS A total of 32 patients with CEA mRNA (+) gastric cancer were enrolled. Twelve patients (37.5%) relapsed; ten showed peritoneal relapse. Three-year survival was similar between the study population and the historical control (67.3% vs. 67.1%, respectively). CONCLUSIONS S-1 monotherapy, which significantly reduced risk for recurrence in stage II/III gastric carcinoma in another phase III trial, seems not to be as effective in eradicating free cancer cells in the abdominal cavity.
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Ito Y, Nakanishi H, Kodera Y, Hirai T, Nakao A, Kato T. Characterization of a novel lymph node metastasis model from human colonic cancer and its preclinical use for comparison of anti-metastatic efficacy between oral S-1 and UFT/ LV. Cancer Sci 2010; 101:1853-60. [PMID: 20500514 PMCID: PMC11159464 DOI: 10.1111/j.1349-7006.2010.01607.x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Although lymph node metastasis (LNM) is the most critical prognostic factor in colorectal cancer patients, the anti-LNM efficacy of chemotherapeutic agents is largely unknown because of the limitations of reproducible human colorectal cancer LNM models. Here, we developed a new LNM model from a recently established colorectal cancer cell line (COLM-5) and compared the anti-LNM efficacy of two oral formulations of 5-fluorouracil (5-FU) derivatives, S-1 and UFT/leucovorin (LV). COLM-5 cells is a poorly differentiated adenocarcinoma cell line with unique features such as left-sided, beta-catenin cytoplasmic localization, and microsatellite stable phenotype. COLM-5 cells expressed vascular endothelial growth factor (VEGF-C) and exhibited peritumoral lymphangiogenesis. Consequently, they showed high LNM potential at an incidence of approximately 90% when subcutaneously injected into nude mice, allowing use for preclinical study. When chemotherapy with S-1 or UFT/LV started from the micrometastasis stage, not the advanced macroscopic metastasis stage, anti-LNM efficacy of S-1 was significantly higher than that of UFT/LV at the dosage in which antitumor activity of the two drugs against primary subcutaneous tumor was comparable. COLM-5 cells showed expression pattern of 5-FU metabolizing enzymes such as high dihydropyrimidine dehydrogenase (DPD) and low thymidylate synthase (TS)/orotate phosphoribosyltransferase (OPRT) both in vitro and in vivo. These results suggest that the preferential anti-LNM activity of S-1 compared with UFT/LV against high-DPD COLM-5 tumors is due to the higher DPD inhibitory activity of 5-chloro-2, 4-dihydroxypyrimidine (CDHP) present in S-1 than uracil in UFT. The COLM-5 model would be an excellent tool for understanding the basic mechanism of LNM and for preclinical study on the anti-LNM efficacy of the drugs.
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Affiliation(s)
- Yuichi Ito
- Division of Oncological Pathology, Aichi Cancer Center Research Institute, Nagoya, Japan
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Yanagita S, Natsugoe S, Uenosono Y, Arigami T, Arima H, Kozono T, Funasako Y, Ehi K, Nakajo A, Ishigami S, Aikou T. Detection of micrometastases in sentinel node navigation surgery for gastric cancer. Surg Oncol 2008; 17:203-10. [PMID: 18539025 DOI: 10.1016/j.suronc.2008.04.008] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Although lymph node metastasis is one of the important prognostic factors for patients with gastric cancer, the clinical significance of micrometastasis remains controversial. In the 6th edition of the TMN classification, micrometastases were classified as micrometastasis (MM) and isolated tumor cells (ITC) according to its greatest dimension. The accurate diagnosis of micrometastases is required when considering less invasive surgery, especially in early stage of gastric cancer. Since generating useful information about micrometastases by conventional RT-PCR is time-consuming, this procedure is not useful for rapid diagnosis during surgery. Recently some new methods of genetic diagnosis have reduced the amount of time required to obtain information about micrometastases in lymph nodes to 30-40 min. Such methodology can be clinically applied during less invasive surgery. The sentinel node (SN) concept has recently been applied to gastric cancer and SN navigation surgery (SNNS) is ideal for reduction of lymphadenectomy in patients with early gastric cancer. However, we should think about some conditions to establish SN concept for gastric cancer: the particle size of radioisotope, relationship between metastatic area and RI uptake, and the diagnosis of micrometastases by various method such as histological examination, immunostaining and RT-PCR. Here, we described the current status of MM and ITC in the lymph nodes and the SN concept in gastric cancer.
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Affiliation(s)
- Shigehiro Yanagita
- Department of Surgical Oncology, Field of Oncology, Course of Advanced Therapeutics, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8520, Japan.
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Yanagita S, Natsugoe S, Uenosono Y, Kozono T, Ehi K, Arigami T, Arima H, Ishigami S, Aikou T. Sentinel node micrometastases have high proliferative potential in gastric cancer. J Surg Res 2007; 145:238-43. [PMID: 17603078 DOI: 10.1016/j.jss.2007.04.037] [Citation(s) in RCA: 51] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2006] [Revised: 03/20/2007] [Accepted: 04/24/2007] [Indexed: 02/07/2023]
Abstract
BACKGROUND The 6th edition of the TNM classification has recently defined "sentinel nodes (SN)," "micrometastasis," and "isolated tumor cells (ITC)." The present study examines the frequency and proliferative activity of such metastases with focus on the SNs of gastric cancer. METHODS We enrolled 133 patients with cT1-2 tumors (cT1: 104, cT2: 29) and mapped SNs. Lymph node metastases were examined by routine histology and by immunohistochemistry with anti-cytokeratin. We used the Ki-67 antibody to detect the primary tumor and lymph node metastases to evaluate proliferative activity. RESULTS The number of patients with SNs metastases and metastatic SNs was 19 and 52, respectively. The frequencies of macrometastasis, micrometastasis, and ITC were 48%, 25%, and 27%, respectively. Ki-67 expression in the tumor closely correlated with lymphatic invasion (P = 0.0001), venous invasion (P < 0.0001), and lymph node metastasis (P < 0.0001). Cells in 96% of macrometastases, 92% of micrometastases, and 29% of ITCs were Ki-67 positive. CONCLUSIONS We showed that micrometastasis and some ITCs in SNs had proliferative activity. We suggest that micrometastasis and ITCs should be removed, especially during SN navigation surgery, until their clinical significance is clarified.
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Affiliation(s)
- Shigehiro Yanagita
- Course of Advanced Therapeutics, Field of Oncology, Department of Surgical Oncology and Digestive Surgery, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.
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