Association of nm23-H1 allelic deletions with distant metastases in colorectal carcinoma

doi:10.1016/0140-6736(91)91444-Y

The Lancet

Volume 338, Issue 8769, 21 September 1991, Pages 722-724

https://doi.org/10.1016/0140-6736(91)91444-Y Get rights and content

Abstract

A prospective study analysed the prognostic value of nm23- H1 allelic deletions in colorectal cancer. Of 21 patients with no evidence of distant metastases at initial operation, 11 showed nm23-H1 allelic deletions (including 1 homozygous deletion); 10 had no nm23-H1 deletions. After median follow-up of 25 months, distant metastases had developed in 8 of 11 (73%) patients with nm23-H1 deletions but in only 2 of 10 (20%) without nm23-H1 deletions (p<0·03). Tests with probe YNZ 22·1, near p53, showed no significant association with distant metastases. nm23-H1 may be, or may be located near, a late-acting suppressor gene in colorectal carcinoma, in which deletions may have prognostic value.

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Cited by (148)

KIBRA (WWC1) Is a Metastasis Suppressor Gene Affected by Chromosome 5q Loss in Triple-Negative Breast Cancer
2018, Cell Reports
Citation Excerpt :
Using a multifaceted approach, we identified KIBRA as a suppressor not only of tumor growth but also of metastasis. Selective pressure for loss of metastasis suppressor genes during tumorigenesis has been described (Al-Mulla et al., 2006; Cohn et al., 1991) and may reflect functional overlap between tumor initiation and aspects of the metastatic cascade. For example, the ability to survive and self-renew could contribute to dissemination and establishment at a secondary site.
Triple-negative breast cancers (TNBCs) display a complex spectrum of mutations and chromosomal aberrations. Chromosome 5q (5q) loss is detected in up to 70% of TNBCs, but little is known regarding the genetic drivers associated with this event. Here, we show somatic deletion of a region syntenic with human 5q33.2–35.3 in a mouse model of TNBC. Mechanistically, we identify KIBRA as a major factor contributing to the effects of 5q loss on tumor growth and metastatic progression. Re-expression of KIBRA impairs metastasis in vivo and inhibits tumorsphere formation by TNBC cells in vitro. KIBRA functions co-operatively with the protein tyrosine phosphatase PTPN14 to trigger mechanotransduction-regulated signals that inhibit the nuclear localization of oncogenic transcriptional co-activators YAP/TAZ. Our results argue that the selective advantage produced by 5q loss involves reduced dosage of KIBRA, promoting oncogenic functioning of YAP/TAZ in TNBC.
Differential expression of the nm23 protein in the progression of oesophageal adenocarcinoma
2003, Pathology
Some studies have shown that abnormalities of the nm23 gene or its expression may be important in tumour dissemination, suggesting that the gene may have metastasis suppressing activity. This study set out to determine if nm23 protein expression is altered with progression and dissemination in oesophageal adenocarcinoma.
Paraffin-embedded, archival tissues of surgical resection specimens of oesophageal adenocarcinoma (n = 46), some of which were accompanied by tissue from areas with high-grade dysplasia (n = 24) and from metastasis in regional lymph nodes (n = 16) were studied. Histologically normal oesophageal glandular tissue (of cardiac-type) (n = 32) obtained from areas of the resections located away from the primary tumour masses and archival tissues of Barrett's metaplasia obtained from endoscopic biopsies (n = 77) were used as non-neoplastic controls. Sections were immuno-histochemically stained by the labelled streptavidin-biotin method using NCL-nm23 antibody.
The total or overall amount of nm23 protein expression paralleled that of cytoplasmic expression and was increased in oesophageal adenocarcinomas (36/46 cases, 78%) when compared with normal oesophageal glandular epithelium (2/32, 6%), Barrett's metaplasia (8/77, 10%) and dysplasia (14/24, 58%). In metastatic carcinoma in regional lymph nodes, overall nm23 expression was similar in proportion (13/16, 81%) to that seen in primary carcinoma. In the analysis of the sequential development of oesophageal adenocarcinoma based on non-neoplastic, preneoplastic and neoplastic archival material, it was found that a high level of overall nm23 expression occurred firstly at the transition from Barrett's metaplasia (8/77, 10%) to dysplasia (14/24, 58%). Nuclear nm23 expression was low in dysplastic tissue (with none of the cases having a high level of nuclear nm23 expression) followed by increased levels as the lesion progressed to invasive adenocarcinoma (13/46, 28%) and metastatic carcinoma in regional lymph nodes (10/16, 63%). However, nm23 expression did not appear to correlate with sex, age, tumour size, extent of tumour infiltration into the oesophageal wall, presence of lymph node metastasis or overall patient survival.
An overall increase in nm23 expression or increase in nm23 expression in the cytoplasm of cells may be important in the early development of oesophageal adenocarcinoma but increased levels of nuclear nm23 occur in its progression to metastatic disease.
Prediction of distant metastases after curative surgery for rectal cancer
2002, Journal of Surgical Research
Background. This study was performed to define selection criteria for adjuvant therapy in rectal cancer.
Materials and methods. An immunohistochemical analysis using nine monoclonal antibodies against CEA, CD15s, CD44v6, DCC, E-cadherin, EGF-R, NM23, PAI-1, and P53 was performed on paraffin sections of two matched (age, gender, UICC stage [I–III], year of operation [1982–1991]) groups of patients (n = 2 × 64) with rectal carcinoma curatively treated by surgery alone. The two groups differed only with regard to metachronous distant metastatic spread. In order to exclude the influence of surgery, all patients had to meet the selection criterion “free of locoregional disease.” Follow-up was prospective (median 80 months). Conventional staining procedures and immunohistochemical evaluation were used. Tumor grading and lymphatic and extramural venous invasion were also investigated. Analysis was performed with Fisher's exact test and Kaplan–Meier estimates of disease-free survival (log rank). The Cox model was used for multivariate analysis.
Results. In univariate analysis only grading (P < 0.001) and extramural venous invasion (P < 0.001) correlated significantly with metachronous metastases. In multivariate analysis, beside grading (P = 0.010) and extramural venous invasion (P = 0.011), CD15s (P = 0.042) was also of significance. All other immunohistochemical markers failed.
Conclusions. The histopathological parameters grading and extramural venous invasion appear to be acceptable predictors of metachronous distant spread in curatively resected rectal cancer. In contrast to the immunohistochemical markers, grading seems to better reflect the individual tumor phenotype and its behavior.
Nm23 protein expression in colorectal carcinoma metastasis in regional lymph nodes and the liver
2001, European Journal of Surgical Oncology
Aims The nm23 gene has been shown to have metastasis suppressing activity and abnormalities of the gene or its expression may be important in tumour progression and dissemination. This study was set out to investigate the possible role of the nm23 in colorectal adenocarcinoma dissemination by examining the level of nm23 protein expression in colorectal carcinoma metastasis in regional lymph nodes and the liver. Methods Using a monoclonal antibody, NCL-nm23 (Novocastra), immunohistochemical expression of the nm23 protein was examined in cases of metastatic colorectal adenocarcinoma in regional lymph nodes (n=71) and liver (n=36). Results The cases of lymph-node metastasis also had tissues from the primary carcinoma (n=71) and matching normal non-neoplastic mucosal tissues (n=71) from the colon and rectum available for the study. More than half of the cases of primary colorectal carcinoma (43/71; 60%) displayed strong nm23 immunoreactivity, with a similar proportion of the lymph-node metastases (40/71 cases; 56%) having strong nm23 immunostaining. However, only a small minority of the normal controls of non-neoplastic colorectal epithelia (12/71 cases; 17%) had strong nm23 immunoreactivity. The difference in nm23 protein expression between normal colorectal mucosa and primary colorectal carcinoma was statistically significant (P=0.0001; chi-squared test with continuity correction). However, no significant difference in nm23 protein expression was found between primary colorectal carcinoma and lymph-node metastases (P=0.81; chi-squared test with continuity correction). Most of the liver metastases (24/36 cases; 67%) had strong nm23 immunostaining but this finding was not statistically significant when compared with that seen in primary colorectal carcinoma (P=0.62; chi-squared test with continuity correction). In addition, nm23 expression was not found to significantly correlate with 5-year survival of patients with liver metastasis (P=0.86), suggesting that it had no predictive value for overall patient survival. There was also no significant correlation between disease recurrence and nm23 expression (P=0.63).Conclusions In summary, increased nm23 protein immunoreactivity is seen in the majority of colorectal carcinomas when compared to normal colorectal tissues but no significant difference in nm23 expression was found between primary colorectal carcinoma and metastatic carcinoma in regional lymph nodes or the liver. This study suggests that increased nm23 expression may be important in early colorectal carcinoma but not in later progression and dissemination of the tumour. In conclusion, the role and importance of the nm23 gene in the development of tumour metastasis in colorectal carcinoma is questionable.
H-ras and Nm23-H1 gene expression and proteolytic ctivity in squamous cell carcinoma of the uterine cervix
2000, Archives of Medical Research
The invasive and metastatic potential of malignant cells results from complex interactions of numerous factors not yet fully understood. Genomic alterations such as ras overexpression and nm23-H1 inhibition have been found to be frequently associated with increased invasiveness in various cancers. On the other hand, secretion of different proteinases are necessary for malignant cells to traverse a network of matrix macromolecules, but the relationship between the genomic alterations and the proteolytic phenotype is still unclear. Our aim was to investigate whether the appearance of the proteolytic phenotype had any correlation with the expression of H-ras and nm23-H1 genes in carcinoma of the uterine cervix.
Twenty-five samples from patients with carcinoma of the uterine cervix at different clinical stages were studied. Cathepsin B1, plasminogen activator, and collagenase activity were assessed in tissue cytosols using specific synthetic oligopeptides as substrates. The expression of H-ras and nm23-H1 was investigated by means of immunohistochemistry and in situ hybridization.
Our results showed that cathepsin B1 was the most consistently elevated proteinase, demonstrating a linear correlation with clinical staging. H-ras expression was found elevated in 40% of the cases. Nm23-H1 protein immunoreactivity was positive in 40% of the cases. No correlation was found among H-ras, cathepsin B1 activity, and survival rate. Among cases with high cysteine proteinase activity, a different clinical behavior depending on the expression of Nm23-H1 was observed. The cases with Nm23-H1 protein had a markedly better survival rate than those lacking this protein. In contrast, the absence of Nm23-H1 in association with high cathepsin B1 activity was a clear indicator of a poor prognosis.
These findings suggest a complex interaction between the proteolytic phenotype and the expression of H-ras and nm23-H1 genes in carcinoma of the cervix that influences the clinical behavior of the tumor.
The role of NM23 in patients with colorectal cancer: A systematic review and meta-analysis
2017, Journal of Huazhong University of Science and Technology - Medical Science

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SHORT REPORTSAssociation of nm23-H1 allelic deletions with distant metastases in colorectal carcinoma

Abstract

Cell

Cell

Regression analysis of prognostic factors in colorectal cancer

J Surg Oncol

Multivariate analysis of pathologic prognostic indicators in large bowel cancer

Cancer

Evidence for a novel gene associated with low tumor metastatic potential

J Natl Cancer Inst

SHORT REPORTS
Association of nm23-H1 allelic deletions with distant metastases in colorectal carcinoma