Metastatic Foci In Lymph Nodes Research Articles

Morphometric Analysis of Lateral Cervical Lymph Node Metastasis in Papillary Thyroid Carcinoma Using Digital Pathology.

Digital pathology uses digitized images for cancer research. We aimed to assess morphometric parameters using digital pathology for predicting recurrence in patients with papillary thyroid carcinoma (PTC) and lateral cervical lymph node (LN) metastasis. We analyzed 316 PTC patients and assessed the longest diameter and largest area of metastatic focus in LNs using a whole slide imaging scanner. In digital pathology assessment, the longest diameters and largest areas of metastatic foci in LNs were positively correlated with traditional optically measured diameters (R = 0.928 and R2 = 0.727, p < 0.001 and p < 0.001, respectively). The optimal cutoff diameter was 8.0mm in both traditional microscopic (p = 0.009) and digital pathology (p = 0.016) evaluations, with significant differences in progression-free survival (PFS) observed at this cutoff (p = 0.006 and p = 0.002, respectively). The predictive area's cutoff was 35.6 mm2 (p = 0.005), which significantly affected PFS (p = 0.015). Using an 8.0-mm cutoff in traditional microscopic evaluation and a 35.6-mm2 cutoff in digital pathology showed comparable predictive results using the proportion of variation explained (PVE) methods (2.6% vs. 2.4%). Excluding cases with predominant cystic changes in LNs, the largest metastatic areas by digital pathology had the highest PVE at 3.9%. Furthermore, high volume of LN metastasis (p = 0.001), extranodal extension (p = 0.047), and high ratio of metastatic LNs (p = 0.006) were associated with poor prognosis. Both traditional microscopic and digital pathology evaluations effectively measured the longest diameter of metastatic foci in LNs. Moreover, digital pathology offers limited advantages in predicting PFS of patients with lateral cervical LN metastasis of PTC, especially those without predominant cystic changes in LNs.

The importance of anatomical localization of non-small cell lung carcinoma in predicting mediastinal lymph node metastasis.

Bronchopulmonary segmental location of non-small lung carcinomas is closely related to metastatic lymph node foci in the mediastinum. Our aim was to investigate the relationship between the anatomical locations of pulmonary masses on the bronchopulmonary segmental base and metastatic lymph node regions in non-small cell lung cancer using preoperative 18F-FDG PET/CT images. Ninety patients newly diagnosed with non-small cell lung carcinoma and referred to PET/CT imaging for staging were included in the study. Tumoral masses that could be evaluated visually and mediastinal node metastases were identified in 18F-FDG PET/CT images, then the relationship between them was investigated statistically. The diagnostic power of 18F-FDG PET/CT of mediastinal nodes was also revealed. Seventy-four males (82.2%) and sixteen females (17.8%) were enrolled in the study. Half of the patients were diagnosed as adenocarcinoma (50%). Investigation of the tumor location and mediastinal metastatic nodes revealed a statistically significant relationship between the apicoposterior segment of the left superior lobe and the left upper and lower paratracheal, subaortic, paraaortic, and left hilar regions according to the IASLC map. The sensitivity, specificity and accuracy of 18F-FDG PET/CT in the mediastinal nodes were 69.2%, 66.6%, and 68%, respectively. There was no statistically significant relationship between tumor location and 8th TNM Stage. Anatomical locations of non-small cell lung carcinomas can affect the disease stage and prognosis because of their tendency to metastasize to some mediastinal regions. However, this relationship needs to be investigated in larger study groups.

Accurately Locating Metastatic Foci in Lymph Nodes With Lugol's Iodine-Enhanced Micro-CT Imaging.

BackgroundAccurate evaluation of lymph node (LN) status is the key factor to determine the treatment and evaluate prognosis for patients with cancer. However, traditional pathological examination resulted in a 30% false-negative rate of detection of metastases in LNs. This study aimed to utilize Lugol’s iodine (I2-IK)-enhanced micro-CT imaging to reveal the 3-dimensional structure of regional LNs and decrease the false-negative rate in pathological examination.MethodsTo explore the feasibility of I2-IK-enhanced micro-CT imaging in locating metastatic lesion in LNs, nonmetastatic and metastatic LNs from mice were used to mimic the imaging process. Then, the LNs from oral squamous cell carcinoma (OSCC) patients were applied to verify the value of I2-IK-enhanced micro-CT imaging in revealing LN structure and locating metastatic lesions in LNs. The glycogen content in nonmetastatic and metastatic LNs was further detected by the use of a glycogen assay kit and periodic acid–Schiff (PAS) staining to explain the imaging differences between them.ResultsIn nude mice, 0.5% I2-IK staining for 4 h was the best parameter for normal LN. The metastatic foci in metastatic LNs were also clearly outlined in this condition. For nonmetastatic LNs from patients with OSCC, 1% I2-IK staining for 12 h was the best parameter. However, due to the increased volume of metastatic LNs, the image effect of 3% I2-IK staining for 12 h was superior to 1% I2-IK staining [tumor background ratio (TBR), 3% vs. 1%, 1.89 ± 0.10 vs. 1.27 ± 0.07, p < 0.001]. Compared with subsequent pathological sections, we found the CT intensity of metastatic foci in LNs and muscle tissues was significantly higher than in nonmetastatic regions. Meanwhile, the glycogen content of metastatic foci in LNs detected was also significantly higher than in nonmetastatic region.ConclusionsI2-IK-enhanced micro-CT imaging could identify the spatial location of metastatic foci in LNs. This will be an effective method to assist in decreasing the LN false-negative rate for cancer pathology.

SOX4 promotes the growth and metastasis of breast cancer

PurposeIncreasing evidence has shown that the transcription factor SOX4 is closely associated with the development and progression of many malignant tumors. However, the effect of SOX4 on breast cancer is unclear. In this study, we purposed to investigate the role of SOX4 in the growth and metastasis in breast cancer and the underlying mechanism. Moreover, the effect of SOX4 on cancer cell resistance to chemotherapeutic agents was also evaluated in vitro and in vivo.MethodsWe used lentivirus technique to ectopically express SOX4 in MDA-MB-231 and SUM149 cells or knockdown SOX4 in BT474 cells, and examined the effect of these changes on various cellular functions. MTT assay was used to determine the cell viability as well as resistance to chemotherapeutic agents. The regulation of SOX4 on epithelial-mesenchymal transition (EMT)-related genes was analyzed using qRT-PCR. The binding of SOX4 to the CXCR7 gene was demonstrated using chromatin immunoprecipitation assay and dual-luciferase reporter activity assay. The effect of SOX4/CXCR7 axis on metastasis was examined using Transwell migration and Matrigel invasion assays. The expression of SOX4/CXCR7 in primary tumors and metastatic foci in lymph nodes was assessed using immunohistochemistry. Cellular morphology was investigated under phase contrast microscope and transmission electron microscopy. Moreover, the effect of SOX4 on tumor growth, metastasis, and resistance to chemotherapy was also studied in vivo by using bioluminescent imaging.ResultsSOX4 increased breast cancer cell viability, migration, and invasion in vitro and enhanced tumor growth and metastasis in vivo. It regulated EMT-related genes and bound to CXCR7 promoter to upregulate CXCR7 transcription. Both SOX4 and CXCR7 were highly expressed in human primary tumors and metastatic foci in lymph nodes. Treatment of breast cancer cells with the CXCR7 inhibitor CCX771 reversed the SOX4 effect on cell migration and invasion. Ectopic expression of SOX4 increased the susceptibility of cells to paclitaxel.ConclusionsSOX4 plays an important role in the growth and metastasis of breast cancer. SOX4/CXCR7 may serve as potential therapeutic targets for the treatment. Paclitaxel may be a good therapeutic option if the expression level of SOX4 is high.

Abstract PD8-10: Regulation of breast tumor metastasis by the dynamic interaction between the TMEM doorway macrophage, tumor and endothelial cells

Abstract Tumor cell intravasation is an essential step in the metastatic cascade, but its exact mechanism is not completely understood. We have previously shown that the direct physical association of a tumor cell over-expressing Mena, a Tie2hi/Vegfhi macrophage and an endothelial cell, creates a micro-anatomic doorway called “tumor microenvironment of metastasis” (TMEM). TMEM are responsible for cancer cell intravasation and dissemination to distant sites. The density of TMEM doorways is a clinically validated prognostic marker of distant metastasis in breast cancer patients. Although we know that TMEM doorways create increased localized vascular permeability which cancer cells utilize to intravasate, the precise molecular mechanisms relating TMEM-doorway function and intravasation has not been elucidated. Active TMEM doorways are found in pre-invasive and invasive ductal breast carcinoma as well as in metastatic foci in lymph nodes and lungs, indicating that TMEM-mediated cancer cell dissemination occurs not only at the primary tumor site but also at metastatic sites, which may perpetuate metastatic dissemination even after removal of the primary tumor. Thus it is essential to understand the exact molecular mechanism of TMEM-doorway function so that specific targeted therapies can be developed to intercept systemic cancer cell dissemination. We outline here the exact molecular mechanism of TMEM-doorway functions. TMEM doorway endothelial cell-secreted Ang2 (a Tie2 ligand) stimulates VEGF expression and production by the Tie2hi TMEM macrophage. Subsequently, the TMEM doorway tumor cell- secreted CSF1 stimulates local secretion of VEGF from the Tie2hi TMEM macrophages, leading to dissociation of endothelial adherens and tight junctions near TMEM and cancer cell intravasation. In addition, we show that acute blockage of CSF1R and Tie2-Ang2 signaling by inhibitors and blocking antibodies both in vitro and in mammary tumors leads to decreased macrophage VEGF production and secretion, decreased tumor cell trans-endothelial migration, and decreased TMEM-dependent vascular permeability, tumor cell dissemination and circulating tumor cells. This is the first description of the molecular mechanisms regulating TMEM doorway function and thus represents a major step in defining new biomarkers and targets for the treatment of metastatic tumors. Citation Format: Chinmay Surve, Allison S. Harney, Mary Chen, Yarong Wang, Xianjun Ye, Yu Lin, Ved Sharma, Richard Stanley, Maja H. Oktay, John S. Condeelis. Regulation of breast tumor metastasis by the dynamic interaction between the TMEM doorway macrophage, tumor and endothelial cells [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr PD8-10.

Tumor Microenvironment of Metastasis (TMEM) Doorways Are Restricted to the Blood Vessel Endothelium in Both Primary Breast Cancers and Their Lymph Node Metastases.

Cancer cells metastasize from primary tumors to regional lymph nodes and distant sites via the lymphatic and blood vascular systems, respectively. Our prior work has demonstrated that in primary breast tumors, cancer cells utilize a three-cell complex (known as tumor microenvironment of metastasis, or TMEM) composed of a perivascular macrophage, a tumor cell expressing high levels of the actin-regulatory protein mammalian enabled (Mena), and an endothelial cell as functional “doorways” for hematogenous dissemination. Here, we studied a well-annotated case–control cohort of human invasive ductal carcinoma of the breast and metastatic lymph nodes from a separate breast cancer cohort. We demonstrate that in primary breast tumors, blood vessels are always present within tumor cell nests (TCNs) and tumor-associated stroma (TAS), while lymphatic vessels are only occasionally present in TCN and TAS. Furthermore, TMEM doorways not only exist in primary tumors as previously reported but also in lymph node metastases. In addition, we show that TMEM intravasation doorways are restricted to the blood vascular endothelium in both primary tumors and lymph node metastases, suggesting that breast cancer dissemination to distant sites from both primary tumors and metastatic foci in lymph nodes occurs hematogenously at TMEM doorways. TMEMs are very rarely detected at lymphatic vessels and do not confer clinical prognostic significance, indicating they are not participants in TMEM-associated hematogenous dissemination. These findings are consistent with recent observations that hematogenous dissemination from lymph nodes occurs via blood vessels.

TM4SF1 is a potential target for anti-invasion and metastasis in ovarian cancer

BackgroundPatients with ovarian cancer commonly have a poor prognosis, owing to its invasiveness and distant metastasis. Studies have found TM4SF1 participates in regulating tumor cell invasion and migration. Therefore, it is expected to become a target for anti-invasion and metastasis in ovarian cancer.MethodsThe expression of TM4SF1 in normal ovarian epithelial tissues, benign ovarian tumor tissues, primary foci of epithelial ovarian cancer and the matched lymph mode metastatic foci was detected using immunohistochemistry to analyze its association with prognosis. The expression of TM4SF1 in HO8910PM, SKOV3 was inhibited using RNAi, and the growth, proliferation, migration, invasion abilities of HO8910PM and SKOV3 cells and the growth of xenograft tumors in nude mice were examined.Results(1) The positive expression rate of TM4SF1 protein in epithelial ovarian cancer tissues (90.90%) was higher than that in benign ovarian tumor tissues (65.22%) and normal ovarian epithelial tissues (31.25%), and both differences were significant (P < 0.05). The expression of TM4SF1 protein was positive in all metastatic lymph node foci and matched primary foci (100%). (2) The level of TM4SF1 protein expression was positively correlated with the International Federation of Gynecology and Obstetrics (FIGO) stage and histological grade. However, The positive TM4SF1 protein expression was not an independent factor of prognosis (P > 0.05). (3) Silencing TM4SF1 expression did not affect growth, proliferation, or cell cycle distribution but inhibited the migration and invasion abilities of HO8910PM and SKOV3 cells. Silencing TM4SF1 expression inhibited the growth of xenograft tumors in nude mice.ConclusionTM4SF1 is a potential target for anti-invasion and metastasis in ovarian cancer.

HER-2/Neu and Hormone Receptor Analysis in Breast Carcinomas and Their Association with Clinicopathologic Parameters.

Invasive breast carcinomas of no special type (IC-NST) are the heterogeneous tumours showing distinct prognostic features even in patients with similar clinicopathological characteristics. To date, many clinicopathological data have been analyzed to make a guess about prognosis and to determine treatment modality. In this study, HER-2/neu status was analyzed by using both immunohistochemical (IHC) and fluorescence in situ hybridization (FISH) methods, and its correlations with hormone receptor status and clinicopathological parameters were investigated. The study was included 112 female patients with diagnosis of IC-NST. FISH for HER-2/neu was applied in only primary tumour tissues, while IHC analyses for HER-2/neu, estrogen (ER) and progesterone receptors (PR) were applied on both primary and metastatic lymph node foci. The results were compared with appropriate statistical methods. Our rates of HER-2/neu overexpression and gene amplification in the overall study group were 22.3 and 25%, respectively. In the metastatic group, these rates were higher than those of the overall study group (34% and 40%, respectively). Gene amplification rate of the axilla positive group was 40%, while this rate in non-metastatic group was 6.7% (p=0.015). Overexpression and amplification results were compliant (χ2=77,591, p<0.001). The concordance rates in HER-2/neu negative and overexpression groups were 95.3% and 88%, respectively. Our false negativity rate was 4.7%. While 36% of score 3+ cases were ER positive, 67.1% of HER-2/neu negative cases showed ER positivity (p=0.01). The increase of gene amplification rate in ER negative cases over 50 years age was more than two times and statistically significant (p=0.014). The concordance rates between the results of IHC and FISH in the HER-2 negative and the overexpression categories were compatible with the literature and lower than the literature, respectively. In the case of ER negativity, the patient's age over 50 years was associated with a higher rate of gene amplification.

The definition of lymph node micrometastases in pathologic N1a papillary thyroid carcinoma should be revised

BackgroundThe aim of this study was to identify the risk factors for structural recurrence with a focus on lymph node–related factors and to determine the optimal cutoff size of lymph node micrometastases in patients with pathologic N1a classical papillary thyroid carcinoma. MethodsWe included patients who underwent total thyroidectomy with central compartment lymph node dissection for classic papillary thyroid carcinoma with pathologic N1a classification. ResultsA total of 398 patients were followed up for a median of 131 months. Structural recurrence occurred in 17.3% of patients (69/398). The multivariate analysis reported the following independent risk factors for structural recurrence: tumor size >1.95 cm, bilaterality, lymphatic and/or vascular invasion, a maximum diameter of the metastatic lymph node focus >3.5 mm, distribution of metastatic lymph node foci size >3.0 mm, and ≥4 metastatic lymph nodes. ConclusionThe newly proposed cutoff of 3.5 mm for a definition of lymph node micrometastasis in pathologic N1a papillary thyroid carcinoma patients can reclassify the risk estimates of structural recurrence, thus modifying postoperative management plans and follow-up strategies.

Comparative Proteomics Uncovers Correlated Signaling Network and Potential Biomarkers for Progression of Prostate Cancer

Background/Aims: Prostate cancer is one of the most common cancers for males worldwide, and it is prone to show the metastatic foci in lymph node and bone with high mortality. To date, the potential mechanism and the corresponding biomarkers for metastatic prostate cancer are still lacking. Hence, our study aims to clarify the mechanism of prostate cancer progression and identify the useful biomarkers for metastatic prostate cancer. Methods: The proteins and network tightly associated with tumor metastasis were identified using quantitative proteomics. Furthermore, the mRNA level of differential expressed proteins were confirmed using qRT-PCR, and the functional cluster analysis was performed using String and Cytoscape. Results: Totally, our study identified 203 differential proteins closely associated with tumor cell migration, and the mRNA expression of those proteins were verified by qPCR. Moreover, the migration associated molecular network was established using bioinformatics analysis. Conclusion: These data raveled the critical proteins for the cell migration of prostate cancer, and identified the potential markers for diagnosing the metastasis of prostate cancer.

FGF4 induces epithelial-mesenchymal transition by inducing store-operated calcium entry in lung adenocarcinoma.

Several fibroblast growth factor (FGF) isoforms act to stimulate epithelial-mesenchymal transition (EMT) during cancer progression. FGF4 and FGF7 are two ligands of FGF receptor 2 (FGFR2). Using two lung adenocarcinoma (ADC) cell lines, A549 and H1299, we showed that FGF4, but not FGF7, altered cell morphology, promoted EMT-associated protein expression, and enhanced cell proliferation, migration/invasion and colony initiation. In addition, FGF4 increased store-operated calcium entry (SOCE) and expression of the calcium signal-associated protein Orai1. The SOCE inhibitor 2,5-di-tert-butylhydroquinone (BHQ) or Orai1 knockdown reversed all of the EMT-promoting effects of FGF4. BHQ also inhibited FGF4-induced EMT in a mouse xenograft model. Finally, 60 human lung ADC samples and 21 sets of matched specimens (primary and metastatic foci in lymph nodes from one patient) were used to confirm the clinicopathologic significance of FGF4 and its correlation with E-cadherin, Vimentin and Orai1 expression. Our study thus shows that FGF4 induces EMT by elevating SOCE in lung ADC.

CRGD-installed polymeric micelles loading platinum anticancer drugs enable cooperative treatment against lymph node metastasis

Lymph node metastasis (LNM) is correlated with decreased survival, indicating high tumor malignancy and being a potential source for subsequent fatal metastases. Targeted therapies inhibiting the formation of LNM, while eliminating established metastatic foci, could provide synergistic effects by reducing the incidence and growth of metastasis. Based on the inhibitory activity of cRGD peptide against the development of metastasis, and the LNM targeting ability of systemically injected drug-loaded polymeric micelles, herein, we studied the capability of cRGD-installed polymeric micelles incorporating the platinum anticancer drug (1,2-diaminocylohexane)platinum(II) (DACHPt) for cooperatively inhibiting the formation and progression of LNM. As cRGD-installed DACHPt-loaded micelles (cRGD-DACHPt/m) presented similar size, drug loading and surface charge to non-conjugated micelles (MeO-DACHPt/m), the differences in the biological performance of the micelles were endorsed to the effect of the ligand. In a syngeneic melanoma model, both MeO-DACHPt/m and cRGD-DACHPt/m showed comparable antitumor activity against the primary tumors and the established metastatic foci in lymph nodes. However, cRGD-DACHPt/m significantly enhanced the efficacy against LNM draining from primary tumors through the effective inhibition of the spreading of cancer cells. This improved inhibition was associated with the ability of cRGD-DACHPt/m to reduce the migration of melanoma cells, which was higher than that of MeO-DACHPt/m, free cRGD and their combination. These results support our strategy of using cRGD-installed micelles for attaining cooperative therapies against LNM exploiting the inhibitory function of the peptide and the cytotoxic effect of the micelles.

Central lymph node metastasis in papillary thyroid microcarcinoma can be stratified according to the number, the size of metastatic foci, and the presence of desmoplasia

Lymph node (LN) metastasis is common in papillary thyroid microcarcinoma (PTMC). The aim of this study was to investigate the impact of LN metastasis and its risk stratification on PTMC recurrence. We retrospectively reviewed the data of 336 patients with PTMC who underwent surgery from 2005 to 2006 at a single institution. LN metastasis was stratified according to the number of metastatic LNs, the ratio of metastatic to removed LNs, the size of metastatic foci in LNs, and the presence of extranodal extension and desmoplasia. Of the 336 patients, 93 (28%) had LN metastasis. During the follow-up of 5.3 years, 16 (4.8%) experienced locoregional recurrence. Among several clinicopathologic factors, LN metastasis was the most important risk factor for recurrence (P = .02). Lateral LN metastasis was correlated with recurrence-free survival (P < .01), whereas central LN metastasis was not (P = .20). When central LN metastasis was stratified, a high number of metastatic LNs (≥3), larger metastatic foci (≥0.2 cm), and the presence of desmoplasia were associated with recurrence-free survival (P < .05). The prognostic significance of central LN metastasis can differ according to the number of metastatic LNs, the size of metastatic foci, and the presence of desmoplasia. Patients with a high number of metastatic LNs, larger metastatic foci, and presence of desmoplasia in LNs should be treated aggressively and supervised carefully for PTMC recurrence.

High MMP-21 expression in metastatic lymph nodes predicts unfavorable overall survival for oral squamous cell carcinoma patients with lymphatic metastasis

The aim of the present study was to examine the clinical significance of lymph node metastatic (LNM) foci in predicting the overall survival of oral squamous cell carcinoma (OSCC) patients with LNM. MMP-21 was screened based on the LNM animal model of OSCC. Then four proteins, matrix metalloproteinase (MMP)-2, MMP-21, vascular endothelial growth factor (VEGF)-C and VEGF receptor (VEGFR)-3 were examined by immunohistochemistry in 63 OSCC specimens, including the primary tumors (PTs) and the corresponding LNM foci. The expression levels between the PTs and LNM foci were compared by Wilcoxon paired test. Relationships between expression of the four proteins and patient overall survival were assessed by Kaplan-Meier based on the median of the labeling index. The Cox proportional hazards model was used to assess the relative hazard factors. MMP-21 and VEGF-C expression levels were higher in the LNM foci than levels in the PTs. Results showed that MMP-2 and VEGF-C expression levels in the PTs and MMP-2, MMP-21 and VEGF-C expression in the LNM foci correlated with the overall survival of the OSCC patients with lymphatic metastasis. MMP-21 expression level in the LNM foci was the most reliable predictor among all the tested factors. These results suggest that high MMP-21 expression in LNM foci can be used to predict survival in OSCC patients with LNM. Characteristics of LNM foci may be more reliable than PT characteristics in predicting the overall survival of OSCC patients with lymphatic metastasis.

Subcutaneous preconditioning increases invasion and metastatic dissemination in colorectal cancer models

Mouse colorectal cancer (CRC) models generated by orthotopic microinjection of human CRC cell lines reproduce the pattern of lymphatic, haematological and transcoelomic spread but generate low metastatic efficiency. Our aim was to develop a new strategy that could increase the metastatic efficiency of these models. We used subcutaneous implantation of the human CRC cell lines HCT116 or SW48 prior to their orthotopic microinjection in the cecum of nude mice (SC+ORT). This subcutaneous preconditioning significantly enhanced metastatic dissemination. In the HCT116 model it increased the number and size of metastatic foci in lymph nodes, lung, liver and peritoneum, whereas, in the SW48 model, it induced a shift from non-metastatic to metastatic. In both models the number of apoptotic bodies in the primary tumour in the SC+ORT group was significantly reduced compared with that in the direct orthotopic injection (ORT) group. Moreover, in HCT116 tumours the number of keratin-positive tumour buddings and single epithelial cells increased at the invasion front in SC+ORT mice. In the SW48 tumour model, we observed a trend towards a higher number of tumour buds and single cells in the SC+ORT group but this did not reach statistical significance. At a molecular level, the enhanced metastatic efficiency observed in the HCT116 SC+ORT model was associated with an increase in AKT activation, VEGF-A overexpression and downregulation of β1 integrin in primary tumour tissue, whereas, in SW48 SC+ORT mice, the level of expression of these proteins remained unchanged. In summary, subcutaneous preconditioning increased the metastatic dissemination of both orthotopic CRC models by increasing tumour cell survival and invasion at the tumour invasion front. This approach could be useful to simultaneously study the mechanisms of metastases and to evaluate anti-metastatic drugs against CRC.

Prognostic Significance of Morphological Distribution of Metastatic Foci in Lymph Nodes with Gastric Cancer

Background/Aims: The morphological distribution of tumor cells in metastatic lymph nodes has been investigated in positive sentinel lymph nodes in several solid cancers. The aim of this study was to clarify the effect of the distribution of metastatic foci in lymph nodes on the prognosis in gastric cancer. Methods: The distribution of metastatic foci in the 100 node-positive patients who had undergone curative gastrectomy were classified into two groups: (1) massive type, in which the tumor occupied the entire lymph node, and (2) non-massive type, in which the tumor did not occupy the entire lymph node. Results: There were 38 patients in the massive type group and 62 patients in the non-massive type group. The 10-year survival rate was significantly poorer in the massive type group (p = 0.001). Multivariate analysis showed that distributional type and nodal status were independent prognostic factors. UICC N stage was subcategorized by distributional type, and survival was shown to be significantly worse in the massive type in the N1 group (p = 0.035). Conclusion: It seems necessary to take the morphological distribution of metastatic foci into consideration when dealing with node-positive patients who had received curative resection for gastric cancer.

Galectin-3 Expression in Tumor Progression and Metastasis of Papillary Thyroid Carcinoma

Galectin-3 plays important roles in cell adhesion, cell proliferation, apoptosis, neoplastic transformation, and metastasis. Galectin-3 expression has been evaluated in various malignant neoplasms to determine its effectiveness in differential diagnosis from benign lesions and its effects on carcinogenesis. There are few and somewhat controversial results regarding its changes through cancer progression in thyroid malignancies. We studied the presence of galectin-3 expression immunohistochemically and its relation with tumor invasiveness and lymph node metastasis in 89 cases of papillary carcinoma of the thyroid. Galectin overexpression was less frequent in cases with lymph node metastases compared with cases without lymph node metastasis (P = 0.001). Metastatic foci in lymph nodes showed a lower degree of galectin-3 overexpression than their primary lesions (P = 0.001). Degree of galectin-3 overexpression was also lower in larger tumors (P = 0.009). Additionally, a decreased level of galectin-3 overexpression was observed at the invasive edges of the tumors (P = 0.001). Galectin-3 overexpression is more profound in early stages of papillary carcinoma, and its expression intensity decreases during tumor progression. This finding is consistent with roles for galectin-3 in cell adhesion to other tumor cells and the matrix.

Establishment and characterization of a cisplatin-resistant cell line (IGSK-1) from a poorly differentiated gastric adenocarcinoma

We successfully established a spontaneously cisplatin-resistant tumor cell line (designated as IGSK-1) derived from original gastric carcinoma. The patient was a 75-year-old Japanese woman. The histopathological diagnosis was gastric poorly differentiated adenocarcinoma accompanied with metastatic foci in lymph nodes, pT3, N2 M0, stage IIIB. The IGSK-1 cells grew as adhesive and monolayered cultures on the bottom of dishes. The susceptibility of the IGSK-1 cells to anti-cancer drugs was examined using oxygen electrode apparatus (Daikin, Tsukuba, JPN), and the results suggested TXL was effective, and CDDP, CPT-11 and 5-FU were not effective. Gastrin and somatostatin secretions were confirmed by immunohistochemical staining and also radioimmunoassay. Immunohistochemistry and radioimmunoassay for serotonin suggested the IGSK-1 cells might incorporate serotonin from the growth media. Spontaneously cisplatin-resistant gastric carcinoma cell line secreted gastrin and somatostatin is very important material for chemotherapy.

Relationship between lymph node metastasis and pathologic features of invasive micropapillary carcinoma of breast

To investigate the relationship between lymph node metastasis and pathologic features of invasive micropapillary carcinoma (IMPC) of the breast. Histopathologic features and status of lymph node metastasis of fifty-one cases of IMPC were studied by microscopic examination, immunohistochemical staining (VEGF-C and VEGFR-3) and analysis of lymphatic vessel density. (1) The number of positive lymph nodes in histologic grade II/III IMPCs was significantly higher (mean 12.5) than that in histologic grade I tumors (mean 4.0). (2) The incidence of nodal metastases in IMPCs with lymphocyte infiltration (+)/(++) was significantly higher (27/28, 96.4%) than that in tumors with no or minimal lymphocyte infiltration (-)/(+/-) (14/23, 60.9%), and the number of positive nodes was also higher (mean 14.4) in tumors with lymphocyte infiltration compared with those without (mean 4.6). (3) In IMPCs with histologic grade II/III, the expression of VEGF-C was significantly higher than that of histologic grade I tumors (P = 0.03). VEGF-C expression was in positive correlation with lymph node metastasis (P = 0.006) and lymphatic vessel density (P = 0.009). Lymph node metastasis was also correlated with lymphatic vessel density (P = 0.007). (4) The percentage of IMPC component in the tumor did not correlate with nodal metastasis. The metastatic foci in lymph node were all IMPC or mainly IMPC. (5) Fourteen of twenty-eight cases (14/28, 50%) of IMPC containing ductal carcinoma in-situ (DCIS) were DCIS of micropapillary type. The histologic grade, lymphatic vessel density and lymphocyte infiltration are key histological features that are correlated with lymph node metastasis of IMPC. The expression of VEGF-C and VEGFR-3 may play an important role in the development of lymph node metastasis of IMPC. Micropapillary type DCIS may be the early stage of IMPC.

The role of microsatellite instability at chromosome 11p15.5 in the progression of breast ductal carcinoma.

The study of microsatellite instability (MSI) has provided the evidence to support asequential, progressive pathway for the development of cancer. In this study, we analyzed the role of MSI at chromosome 11p15.5 using microdissection of paraffin-embedded tissue from 68 matched normal and breast tumor samples. Components of intraductal, invasive and metastatic foci in lymph node were assessed for MSI using the polymorphic markers D11S922, tyrosine hydroxylase (TH) and D11S988. We found that MSI at D11S922 was relatively high incidence than other two markers and increased during breast cancer progression. The overall frequency of MSI at D11S922 was 26.7% in pure intraductal carcinoma, 36.4% in invasive carcinoma, and 40.0% in invasive carcinoma with metastases. We observed no significant correlation between MSI at chromosome 11p15.5 and the patient's age, tumor size, histological grade, or lymph node metastasis. We compared the MSI incidence with the expression of prognostic markers, such as p53, c-erb B2, estrogen receptor, and progesterone receptor, and found no significant correlation. We suggest that the MSI of chromosome 11p15.5 is increased during breast cancer progression, but long-term follow-up study would establish whether MSI at chromosome 11p15.5 could be useful as a potential prognostic marker for breast cancer.