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PubMed2004

Suppression of metastasis by nuclear factor kappaB inhibitors in an in vivo lung metastasis model of chemically induced hepatocellular carcinoma.

To evaluate the suppressive effects of nuclear factor kappa B (NF-kappaB) inhibitors on metastasis, three agents, pentoxifylline (PTX, 0.5% in diet), N-acetyl-L-cysteine (NAC, 0.5% in diet), and aspirin (ASP, 0.5% in diet) were applied in an in vivo highly metastatic rat hepatocellular carcinoma (HCC) model in F344 male rats. Administration of NF-kappaB inhibitors for 8 weeks after induction of highly metastatic HCC by sequential treatment with diethylnitrosamine and N-nitrosomorpholine did not cause any significant change in survival rate or body weight. The incidence of HCC was 100% at week 23, regardless of treatment with NF-kappaB inhibitors. PTX, NAC, and ASP did not exert any significant effect on the development or differentiation of HCCs, although PTX tended to decrease the multiplicity of HCC. Although no lung metastasis was observed in the rats killed at the end of the period of carcinogen exposure, lung metastasis was found in 100% of animals in all the groups at the end of the experiment. Multiplicity of lung metastasis was significantly decreased by PTX and NAC, whereas ASP was without significant influence. The size of metastatic nodules was also significantly reduced in the PTX treatment group. Furthermore, the inhibitory kappa-B (IkappaB) protein level, considered to be a marker for the degree of NF-kappaB transcription, was significantly suppressed by PTX. mRNA expression in HCC for vascular cell adhesion molecule-1 (VCAM-1), which is considered to play a key role in attachment of cancer cells to the endothelium, was significantly suppressed by PTX. Among the splicing variants of VEGF, VEGF-A120, VEGF-A144, VEGF-A164, and VEGF-A188, suppressed mRNA expression of VEGF-A188 appeared to be correlated with suppression of lung metastasis formation. In conclusion, the present study demonstrated that NF-kappaB inhibitors have the potential to inhibit lung metastasis from rat HCCs in vivo, and PTX is especially promising. Its mechanism of action may involve suppression of VCAM-1 and VEGF-A188 production.

Acetylcysteine↗
PubMed2004

KAI1 COOH-terminal interacting tetraspanin (KITENIN), a member of the tetraspanin family, interacts with KAI1, a tumor metastasis suppressor, and enhances metastasis of cancer.

We cloned recently an alternatively spliced variant of KAI1 mRNA that lacked exon 7 at the COOH-terminal region and showed differences in metastasis suppression when compared with the wild-type KAI1. These findings indicated that the COOH-terminal region of KAI1 is critical for its metastasis suppressor function. In this study, we isolated a cDNA clone of VANGL1, a member of the tetraspanin protein family, which interacted specifically with the COOH-terminal cytoplasmic domain of KAI1 in the yeast two-hybrid system. We renamed it KAI1 COOH-terminal interacting tetraspanin (KITENIN). We found that KITENIN-overexpressing CT-26 mouse colon cancer cells showed increased tumorigenicity and early hepatic metastasis in vivo, as well as increased invasiveness and adhesion to fibronectin in vitro compared with parental cells. Moreover, increased levels of KITENIN were observed in a human gastric tumor and its metastatic tissues, compared with the normal adjacent mucosa. Our results indicate that KITENIN promotes adhesion and invasion of cancer cells in vitro and in vivo, and suggest that KITENIN participates in the regulation of the tumor formation and metastasis by interacting with KAI1, a metastasis suppressor and antisense KITENIN strategy that can be used to inhibit metastasis in various cancers.

Alternative Splicing↗
PubMedDate not supplied

[Evaluation of occult lymph node metastasis in lower lip cancers and approach to N(0) neck metastasis].

OBJECTIVES: In this study, we evaluated the incidence of occult lymph node metastasis and the approach to N0 necks in carcinoma of the lower lip. PATIENTS AND METHODS: Sixty-eight patients who underwent surgery for squamous cell carcinoma of the lower lip were monitored for a minimum period of three years. All the patients were males (mean age 54 years; range 36 to 69 years). Preoperatively, 15 and 53 patients had N+ and N0 necks, respectively. Depending on the tumor localization, unilateral or bilateral suprahyoid neck dissections were performed. Nine patients underwent radical neck dissection following detection of metastasis on histopathologic examination. RESULTS: Histopathologic examination revealed metastasis in four patients (4/15; 26%) with N+ necks and in five patients (5/53; 9.4%) with N0 necks. Four patients (6.7%) developed late cervical lymph node metastasis at level 3. No evidence of neck disease was encountered in 93% of patients. CONCLUSION: Suprahyoid neck dissection appears to be effective in detecting occult lymph node metastasis. With improved surgical and histopathologic techniques and consideration of skip metastasis, more aggressive treatment approaches may be employed and better survival rates may be obtained.

Adult↗
PubMed2002

Cystatin-like metastasis-associated protein mRNA expression in human colorectal cancer is associated with both liver metastasis and patient survival.

PURPOSE AND EXPERIMENTAL DESIGN: We previously reported that an increased expression of cystatin-like metastasis-associated protein (CMAP) mRNA is involved in liver-specific metastasis in a mouse model. We also identified its human homologue and showed that the expression of CMAP in various human cancer cell lines correlated with the description of malignancy in these cell lines. However, there is still no information available on the clinical significance of CMAP expression in human cancer specimens. Thus, we studied the CMAP expression levels using a real-time quantitative reverse transcription-PCR for 79 patients with colorectal cancer, including 17 cases with liver metastasis. RESULTS: The mean expression level of CMAP in tumor tissue specimens was significantly higher than in the corresponding normal tissue specimens (P < 0.05). A higher expression of CMAP was significantly correlated with liver metastasis (P < 0.01) as well as with a less differentiated histological type (P < 0.05) of colorectal cancer. An increased expression of CMAP was also identified as the strongest independent factor for liver metastasis based on a multivariate analysis (P < 0.001). Furthermore, the prognosis of the patients with a higher expression of CMAP was significantly worse than those with a lower expression (5-year survival rate; 49.7% and 75.0%, respectively, P = 0.038). CONCLUSIONS: These findings imply that the expression level of CMAP in human cancer may be a new biomarker for both liver metastasis and the patient's outcome.

Aged↗
PubMed1996

[Molecular mechanisms of cancer metastasis--ets-related nuclear transcription factor play an important role in cancer metastasis].

Significant progress has been made in the field of cancer metastasis, and the molecular mechanism of cancer metastasis is being studied extensively. Recent studies revealed that some oncogenes and metastasis-associated genes play important roles in cancer metastasis. Some nuclear transcription factors have appeared to be involved in this metastasis. Ets-related E1AF confers the invasive phenotype on cancer cells. E1AF that acts as a transcription factor is believed to play an important role in cancer invasiveness/metastasis through transcriptions of metastasis-related genes.

Animals↗
PubMed1997

Extracapsular invasion of lymph node metastasis is an indicator of distant metastasis and poor prognosis in patients with thyroid papillary carcinoma.

BACKGROUND: In patients with thyroid papillary carcinoma, age and the presence or absence of distant metastasis are regarded as the main prognostic factors. However, the histologic characteristics of thyroid papillary carcinoma that develops distant metastasis have not yet been clarified. METHODS: The histologic findings and prognosis of 50 patients with thyroid papillary carcinoma who later developed distant metastasis (metastatic group) were compared with those of 50 patients without local recurrence or distant metastasis (control group). The age, tumor size, and gender ratio of the control group were matched with those of the metastatic group. Univariate analyses (chi-square test and/or Fisher's exact test) and multivariate analyses (logistic regression) were performed. RESULTS: Univariate analyses showed that the incidence of nonpure papillary carcinoma, absence of bone at the periphery of the tumor, invasion of the perithyroidal muscle, large lymph node deposits, and extranodal invasion were significantly higher in the metastatic group. Multivariate analyses revealed that only extranodal invasion was statistically significant (P = 0.0045) and that the odds ratio of extranodal invasion in distant metastasis was 9. Moreover, the risk of death from thyroid carcinoma was higher among the patients with extranodal invasion than those without (P <0.01). CONCLUSIONS: The presence of extranodal invasion in patients with thyroid papillary carcinoma is an indicator of distant metastasis and poorer prognosis.

Adult↗
PubMed1997

Treatment and outcome of brain metastasis as first site of distant metastasis from breast cancer.

Twenty-eight consecutive patients with breast cancer were analyzed who presented with a single brain metastasis as first site of distant metastasis. The response to surgery with postoperative radiation therapy (RT) (9 patients) and to non-surgical therapy as first-line treatment was 100% and 89% respectively with a significant difference in median recurrence-free intervals of 23 months and of 5 months respectively (p = 0.033). Retreatment of a local relapse by surgery (+/-RT, +/-chemotherapy) or by non-surgical treatment resulted in a response in 6 of the 7 operated patients and in 5 of the 6 non-operated patients with a median duration of response of 7 months (range 2-20 months) and of 3 months (range 2-4 months) respectively. The overall median survival of the 28 patients with a single brain metastasis was 16 months (range 2-39 months). The median survival in the primarily operated patients was 23 months, in the primarily not-operated group 10 months, and in the never-operated group 9 months. In comparison, the response to non-surgical treatment in 20 consecutive patients who presented with multiple brain metastases as first site of distant metastasis was 55% with a median recurrence free interval of 4 months. The median survival in this group was 4 months, which was significantly shorter than survival of patients with single brain metastasis (p = 0.0036). These results suggest that breast cancer patients with a single brain metastasis as first presentation of relapse constitute a specific subgroup with a favorable response to treatment and a long survival especially if they can be treated by surgery with postoperative RT.

Adult↗
PubMed1991

[Studies on pulmonary metastasis of renal cell carcinoma--pulmonary embolism revealed by lung-perfusion imaging and metastasis].

Invasion of renal cell carcinoma to veins is known to have a close relation with pulmonary metastasis. We speculated that a tumor thrombus would lodge in the pulmonary artery before establishment of a clinically apparent pulmonary metastasis. This may be particularly true in patients with renal vein or vena cava involvement of renal cell carcinoma. In this instance, it is crucial to know the clinical consequence of tumor thrombi in the pulmonary artery. Thus, we investigated these issues with the aid of lung-perfusion imaging in 22 renal cell carcinoma patients with and without vein involvement. The lung-perfusion imaging revealed positive in 8 of the patients examined prior to treatment. The incidence of positive finding was well correlated with an extensive vein invasion. Patients with positive imaging prior to treatment were associated with pulmonary metastasis at a higher rate than those with negative findings. These findings have indicated that vein invasion should be related with tumor thrombus formation in the pulmonary artery, and such a status in the lung would, in part, result in pulmonary metastasis. Two different clinical courses were found by an analysis of patients with the positive imaging prior to treatment. One is the clinical course in which positive findings were correlated with a newly developed metastasis in the lung. Thus, care should be taken in development of the metastasis during the follow-up when patients show the positive lung-perfusion imaging prior to treatment. On the other hand, we found two patients in whom the positive findings disappeared during the follow-up.

Adult↗
PubMed1996

[Principles of lymphogenic and hematogenous metastasis and metastasis classification].

The process of lymphatic and hematogenous metastasis has been elucidated in recent years by thorough morphological studies on resection specimens and new findings in the field of molecular biology. However, this process is far from being completely understood. Metastasis is a multistep process requiring numerous interactions of tumor cells with the surrounding matrix. Especially, adhesion, invasion of basement membranes and passage through extracellular matrix are active processes taking place in the tissue of the primary tumor and later on in host tissues. Metastases to distant organs can be the result of a venous invasion of the primary tumour as well as lymphovenous short-circuits or by the thoracic duct. Using immunohistological methods, tumor cells can be detected in lymph nodes, blood and bone marrow. This not termed metastasis, these cells are classified as isolated tumor cells (M1(i)). The frequency of lymph node metastasis depends on the intensity of histological examination. In colorectal carcinomas the risk of metastatic lymph nodes can be estimated by conventional parameters such as pT category of the primary tumor, histological grade or invasion of lymphatic vessels. The benefit of applying molecular markers (such as nm23-H1) is unclear. The successful removal of hepatic metastasis of colorectal carcinomas requires a more precise classification. A proposal of a more detailed and clarified classification will be discussed.

Humans↗
PubMed2004

Predictors of nonsentinel node metastasis in patients with breast cancer after sentinel node metastasis.

HYPOTHESIS: The presence of nonsentinel lymph node (NSLN) metastasis after having a positive sentinel lymph node dissection finding is associated with tumor size and stage, the presence of lymphovascular invasion, micrometastasis, and extranodal extension. DESIGN: Retrospective case series. SETTING: University hospital. PATIENTS: Four hundred seven consecutive patients at a single institution who underwent sentinel lymph node dissection as part of breast conservation or mastectomy with biopsy-proved cancer. INTERVENTION: Completion axillary lymph node dissection and definitive therapy. MAIN OUTCOME MEASURES: Sentinel node metastasis, NSLN metastasis, tumor size and stage, lymphovacular invasion, micrometastasis, extronodal extension, histological tumor characteristics, and number of sentinel nodes removed. RESULTS: In a univariate analysis, size of the primary tumor and extranodal extension were associated with having positive NSLN findings. The presence of micrometastasis was associated with negative NSLN findings. When all factors were included in a logistic regression analysis, the significant predictor of NSLN metastasis was extranodal extension (P =.002). Lymphovascular invasion was not associated with positive NSLN findings (P =.11). The number of sentinel nodes removed also had no bearing on the status of the NSLNs (P =.37). CONCLUSIONS: Although primary tumor size and micrometastases correlate with the status of the NSLNs, extranodal extension is the most important independent predictor of NSLN metastasis. These findings may ultimately spare patients a full axillary lymph node dissection. However, pending results of larger clinical trials, full axillary lymph node dissection is still recommended for patients with sentinel lymph node metastases.

Adult↗
PubMed1981

Clonal variation and functional correlation of organ-specific metastasis and an organ-specific metastasis-associated antigen.

Monoclonal antibodies were used to probe the cell surface of organ-selected metastatic variant cells. Previously we defined a liver metastasis-associated antigen (LMAA) by means of the reaction of a monoclonal antibody with a liver metastasis selected tumour variant cell line, MDCC-AL2. The monoclonal anti-LMAA antibodies specifically inhibit liver metastasis of AL2. There is a correlated, clonal variation in LMAA expression and liver metastasis in both the AL2 cell line and an overy-selected metastatic variant MDCC-AL3. The variation in liver metaatatic ability is thought to represent clonal progression of the tumour cell lines. The LMAA probably represents only one of the ways in which a tumour cell may give rise to a live metastasis. Two hypotheses are discussed utilizing the LMAA in a functional role in the specific trapping of metastatic tumour cells in the liver or the successful colonization of the liver by metastatic tumour cells.

Animals↗
PubMed2002

Suppression of human melanoma metastasis by the metastasis suppressor gene, BRMS1.

We recently identified a novel metastasis suppressor gene, BRMS1, in breast cancer. Since the BRMS1 gene maps to chromosome 11q13.1-q13.2 and since chromosome 11q defects have been described in various stages of human melanoma progression, we hypothesized that BRMS1 may function as a tumor or metastasis suppressor in melanomas as well. Quantitative real-time RT-PCR revealed that BRMS1 mRNA expression was high in melanocytes, considerably reduced in early melanoma-derived cell lines, and barely detectable in advanced/metastatic cell lines. Stable transfectants of BRMS1 in the human melanoma cell lines MelJuSo and C8161.9 did not alter the tumorigenicity of either cell line, but significantly suppressed metastasis compared to vector-only transfectants. Orthotopic tumors continued to express BRMS1, but expression was lost in lung metastases. In vitro morphology, growth rate, and histology of BRMS1 transfectants were similar to controls. BRMS1 transfectants were less invasive in a collagen sandwich assay and had restored homotypic gap junctional intercellular communication (GJIC). Thus, BRMS1 functions as a metastasis suppressor in more than one tumor type (i.e., breast carcinoma and cutaneous melanoma) by modifying several metastasis-associated phenotypes.

Animals↗
PubMed2006

The DARC side of metastasis: shining a light on KAI1-mediated metastasis suppression in the vascular tunnel.

Tumor cell metastasis to distant organs is an inefficient process that is limited in part by recently identified metastasis suppressors. Interactions between tumor cells and the surrounding stroma are thought to control much of cancer progression. In the August issue of Nature Medicine, demonstrate that specific cell surface interactions between the metastasis suppressor KAI1 on tumor cells and the decoy cytokine receptor DARC on adjacent vascular cells triggers senescence in the tumor cells and suppresses metastasis. These new observations demonstrate how metastasis suppressors can relay the restraint imposed by the stroma onto disseminating tumor cells.

Animals↗
PubMed2004

Identification of metastasis-associated proteins through protein analysis of metastatic MDA-MB-435 and metastasis-suppressed BRMS1 transfected-MDA-MB-435 cells.

BRMS1 (breast cancer metastasis suppressor 1) was recently identified as a novel breast cancer metastasis suppressor gene. To further characterize BRMS1-mediated metastasis suppression, we applied two-dimensional proteomic and mass spectrometry (LC-tandem MS and MALDI-TOF) analysis to identify proteins differentially expressed between highly metastatic MDA-MB-435 cells and metastasis-suppressed BRMS1-transfected MDA-MB-435 cells. Quadruplicate independent 2D gels were run and analyzed under identical conditions. Following in-gel trypsin digestion of seven differentially expressed proteins, amino acid sequence and mass profiles of the peptides were generated. Proteins were identified from the NCBI non-redundant database using the search program TurboSequest. Differential expression was confirmed for five proteins, including annexin I and alpha B-crystallin, by Northern blot analysis and immunostaining. Furthermore, we showed that both proteins were expressed in vivo in lungs containing metastasized MDA-MB-435 cells but not expressed in normal lung tissue of athymic mice. Our results suggest that annexin I and alpha B-crystallin are important cellular proteins that are down regulated through BRMS1 mediated metastasis suppression.

Amino Acid Sequence↗
PubMed2005

Expression of the breast cancer metastasis suppressor gene, BRMS1, in human breast carcinoma: lack of correlation with metastasis to axillary lymph nodes.

The BRMS1 (breast cancer metastasis suppressor 1) gene has been found to suppress metastasis in animal models without inhibiting primary tumor growth. The aim of this study was to measure expression of BRMS1 mRNA in a panel of human breast carcinomas and compare its expression with parameters of local dissemination such as tumor size and lymph node metastasis. We also compared expression of BRMS1 mRNA in normal breast tissue, fibroadenomas, primary breast cancers and axillary nodal metastases from primary breast cancers. BRMS1 mRNA was detected in 10/11 (90%) specimens of normal breast tissue, 12/16 (75%) fibroadenomas, 64/82 (78%) primary breast cancer and 11/15 (64%) lymph node metastases (p, NS). In the primary cancer, expression was independent of tumor size, tumor grade, metastasis to axillary nodes and hormone receptor status. Furthermore, similar levels of BRMS1 were found in normal breast tissue, primary breast carcinomas and lymph node metastases from primary breast cancer. Our results do not suggest a role for BRMS1 in suppressing metastasis to local lymph nodes in patients with breast cancer.

Axilla↗
PubMed2006

Prognosis of breast cancer after supraclavicular lymph node metastasis: not a distant metastasis.

BACKGROUND: We performed this study to analyze the survival of breast cancer patients with isolated supraclavicular lymph node metastasis (SLNM) and assess whether SLNM is distant metastasis or not. METHODS: Sixty-three patients who developed an isolated SLNM among 3170 primary breast cancer patients between 1990 and 1999 were enrolled. The survival after SLNM was compared with that of 151 patients who developed local recurrences and 599 who had distant metastasis and was analyzed according to different levels and numbers of positive axillary nodes. RESULTS: Thirty-five of the 63 patients died during a median follow-up of 58.3 months. The 5-year overall survival (OS) rates after SLNM, local relapse, and distant metastasis were 33.6%, 34.9%, and 9.1%, respectively. The 5-year OS for patients with involved nodes confined to axillary level I was 74.4%, which was significantly better than that for involved nodes in level II or III or SLNM (49.2%, 52.8%, and 33.6%, respectively; P < .0001). For one to three positive axillary nodes, the 5-year OS was 83.2%, which was significantly better than that for four to nine positive nodes, more than nine positive nodes, and SLNM (62.6%, 42.3%, and 33.6%, respectively). There was no significant difference between SLNM and more than nine positive nodes. Surgical removal of the supraclavicular nodes was a significantly better prognostic factor for OS after SLNM (P = .0327). CONCLUSIONS: The 5-year OS after supraclavicular nodal metastosis, local relapse, and distant metastasis were 33.6%, 34.9%, and 9.1%, respectively. Good neck control either by surgery or chemotherapy achieved better survival.

Adult↗
PubMed1999

[Cervical lymph node metastasis and blood metastasis of thyroid cancer].

OBJECTIVE: To evaluate the relevant factors for lymph cervical node metastases and blood metastases of thyroid cancer and to raise the level of diagnosis and treatment. METHODS: 225 cases of thyroid cancer were treated from Jan. 1984 to Dec. 1992. Their clinical characteristics, treatment, and pathologic features were described. RESULTS: The metastasis of thyroid cancer was related to its pathologic and invasive features. Papillary and squamous cell carcinomas were characterized by local lymph metastasis. Their metastasis rate was 44.7%, and 3/3 respectively. Follicular carcinoma showed good differentiation but vessel metastasis with a metastatic rate of 18.2%. The metastasis rate was high and the prognosis poor, in undifferentiated cancer. CONCLUSIONS: Better treatment results may be achieved if proper management of thyroid cancer is based on its pathologic type and extent of local infiltration.

Adenocarcinoma, Follicular↗