Tumor metastasis is the leading cause of death in cancer patients. From a series of tumorcohort studies, low expression of Nm23/NDP kinase has been correlated with poor patientprognosis and survival, lymph node infiltration, and histopathological indicators of highmetastatic potential in a number of cancer types, including mammary and ovarian carcinomas andmelanoma. In other tumor types, no correlation has been established. Transfection ofNm23/NDP kinase cDNA into highly metastatic breast, melanoma, prostrate and squamous cellcarcinomas, and colon adenocarcinoma cells significantly reduced the metastatic competencyof the cells in vivo. In culture, cell motility, invasion, and colonization were inhibited, whereastumorigenicity and cellular proliferation were not affected, indicating that Nm23/NDP kinaseacts as a metastasis suppressor.

Nm23/nucleoside diphosphate kinase in human cancers.

Clinical implications of the ErbB/epidermal growth factor (EGF) receptor family and its ligands in ovarian cancer.

Expression of c-erbB3 protein was investigated in 104 primary breast carcinomas comprising nine comedo ductal carcinoma in situ (DCIS), 91 invasive ductal carcinomas and four invasive lobular carcinomas using two monoclonal antibodies, RTJ1 and RTJ2. Of the 91 invasive ductal carcinomas, seven contained the comedo DCIS component adjacent to the invasive component. An immunohistochemical technique was used to evaluate the association between expression of c-erbB3 and clinical parameters and tumour markers such as epidermal growth factor receptor (EGFR), c-erbB2, cathepsin-D and p53 in archival formalin-fixed paraffin-embedded tumour tissues. Our results indicated that RTJ1 and RTJ2 gave identical staining patterns and concordant results. It was found that the overexpression of c-erbB3 protein was observed in 67% (6/9) of comedo DCIS, 52% (44/84) of invasive ductal carcinomas, 71% (5/7) of carcinomas containing both the in situ and invasive lesions and 25% (1/4) of invasive lobular carcinomas. A significant relationship (P < 0.05) was observed between strong immunoreactivity of c-erbB3 protein and histological grade, EGFR and cathepsin-D, but not with expression of c-erbB2, p53, oestrogen receptor status, lymph node metastases or age of patient. However, we noted that a high percentage of oestrogen receptor-negative tumours (59%), lymph node-positive tumours (63%) and c-erbB2 (63%) were strongly positive for c-erbB3 protein. We have also documented that a high percentage of EGFR (67%), c-erbB2 (67%), p53 (75%) and cathepsin-D-positive DCIS (60%) were strongly positive for c-erbB3. These observations suggest that overexpression of c-erbB3 protein could play an important role in tumour progression from non-invasive to invasive and, also, that it may have the potential to be used as a marker for poor prognosis of breast cancer.

Expression of c-erbB3 protein in primary breast carcinomas.

Tumor invasion as dysregulated cell motility

The erbB-3 gene encodes a transmembrane protein that is related to the epidermal growth factor (EGF) receptor and erbB-2. We compared erbB-3 expression in the normal human pancreas, human pancreatic carcinomas, and cultured human pancreatic cancer cell lines. Northern blot analysis of total RNA revealed the anticipated 6.2-kb mRNA transcript in all 19 normal pancreatic samples. In 17 of 27 pancreatic cancers, there was a 6.7-fold increase (P < 0.001) in erbB-3 mRNA levels. Southern blot analysis did not reveal erbB-3 gene amplification. Four of six pancreatic cancer cell lines exhibited the 6.2-kb erbB-3 mRNA transcript, and all four cell lines coexpressed the epidermal growth factor receptor and erbB-2. Using a highly specific antibody, we determined that faint to moderate erbB-3 immunoreactivity was present in the ductal cells in the normal pancreas. In 47% (27/58) of the pancreatic cancers, there were many cancer cells with intense erbB-3 immunostaining. The presence of erbB-3 in the cancer cells was associated with advanced tumor stage and shorter survival postoperatively. These data indicate that a significant proportion of human pancreatic cancers overexpress erbB-3, and that erbB-3 may contribute to disease progression in this disorder.

https://clincancerres.aacrjournals.org/content/clincanres/1/11/1413.full.pdf

Enhanced erbB-3 expression in human pancreatic cancer correlates with tumor progression.

To verify the role of metastasis-related nm23 genes in carcinogenesis and progression of ovarian carcinoma, we analyzed the mRNA levels of the nm23 genes of both isoforms, - H1 and - H2 , together with those of the epidermal growth factor receptor, the c- erb B-2, and the c- erb B-3 genes in 45 ovarian carcinomas and 5 benign cystadenomas. Expressions of nm23 gene products/nucleoside diphosphate kinases, epidermal growth factor receptor, erbB-2 protein, and sex steroid receptor status in ovarian carcinomas were also examined by immunohistochemistry. The mRNA levels of nm23-H1 and nm23-H2 were higher in carcinoma tissues compared with benign tumors ( H1, P < 0.01). The mRNA levels of c- erb B-2 and c- erb B-3 were also elevated in carcinoma tissues, and there was a positive correlation between mRNA levels of the nm23-H1 and the c- erb B-2 genes ( r = 0.58; P < 0.05). Correlation of immunohistochemical staining between nucleoside diphosphate kinases and erbB-2 protein was also observed in ovarian carcinoma tissues. Sex steroid receptor positivity was related to a higher expression of nucleoside diphosphate kinases. Expression levels of the nm23 genes in ovarian carcinomas were not related to either histological subtype or local extension and peritoneal dissemination. Among stage III ovarian carcinomas, however, tumors possessing lymph node metastasis showed significantly lower nm23-H1 mRNA levels than those without nodal involvement ( P < 0.05). Stage IV carcinomas also exhibited lower nm23-H1 and nm23-H2 expression levels compared with other stages ( P < 0.05). These results suggest that expression of the nm23 genes, especially nm23-H1 , is activated, accompanied by c- erb B-2 and c- erb B-3 overexpressions, in early stages of the carcinogenic process of ovarian carcinoma and reduction of nm23-H1 expression occurs in association with lymph nodal and/or distant metastasis.

http://cancerres.aacrjournals.org/content/canres/54/7/1825.full.pdf

Expression of Metastasis-related nm23-H1 and nm23-H2 Genes in Ovarian Carcinomas: Correlation with Clinicopathology, EGFR, c-erbB-2, and c-erbB-3 Genes, and Sex Steroid Receptor Expression

Shinji Arao

Papers

Expression of Metastasis-related nm23-H1 and nm23-H2 Genes in Ovarian Carcinomas: Correlation with Clinicopathology, EGFR, c-erbB-2, and c-erbB-3 Genes, and Sex Steroid Receptor Expression