Aberrant expression of Met receptor in cancers

As summarized in Table 3, overexpression of the Met receptor was noted in a wide variety of tumour cells and tissues, including carcinoma, lymphomas, and soft tissue tumours. Moreover, it should be emphasized that the level of Met receptor expression tends to correlate with the progression of tumours in many types of tumours; a higher expression of the Met receptor is seen in the late stage or in metastatic tumours. Over-expressed Met receptor in advanced tumour tissues may be activated by HGF, which results in acquisition of malignant behavior in many types of tumour cells. Alternatively, the Met receptor may be activated in a ligand-independent manner in some tumours wherein Met expression is extremely high, through increased susceptibility to ligand-independent receptor dimerization. In addition, the result indicate that analysis of Met receptor expression in primary tumour tissues probably relates to the prognosis of tumour malignancy (also see below).

At least two distinct mechanisms by which the Met receptor is over-expressed in cancers could be considerable, i.e., transcriptional activation or amplification of the c-met gene. In case of colorectal cancers, over-expression of the Met receptor was related to transcriptional activation in 90% of the primary tumours, whereas 8 among 9 cases of metastases of colorectal cancers accompanied amplification of c-met gene (189). Amplification of the c-met gene may possibly occur more frequently in late stage metastatic tumours than in primary tumours, presumably due to chromosomal instability in advanced cancers.

Table 3, Expression of Met receptor in cancers_

Type of tumour Expression of Met receptor References

Bladder carcinoma over-expressed 185

Bone tumours

Osteosarcoma over-expressed 164, 186, 187

Rhabdomyosarcoma expressed 186

Chondrosarcoma expressed 187

Histiocytoma expressed 187

Breast carcinoma over-expressed; higher levels in poorly 47, 169

differentiated tumours

Colorectal cancer over-expressed; higher in metastatic tumours 188, 189

gene amplification in 10% carcinomas and 8/9 in 189 metastases

Endometrial carcinoma higher expression in late stage tumours 190

Esophageal SCC highlyexpressed;higherexpressioninmetastatic 191

tumour

Esophangeal carcinoma expressed 58

Gastric cancer over-expressed and related to the increase in 62, 192

disease state; over expressed and higher in diffuse and high grade invasive cancers

Glioblastoma expressed 68,72, 165

Glioma over-expressed 170

Giant cell tumour over-expressed 186

Hepatocellular carcinoma over-expressed; higher expression correlated 172, 193-199

with growth 200 correlated with poor prognosis

Hepatoblastoma over-expressed 201

Kaposi's sarcoma highly expressed; 78,79

induction of HGF and Met by IL-1 202

Laryngeal carcinoma over-ex pre ssedcorrelated with lymphonodc 203

metastasis

Leukemia over-expressed 80,81

Lung carcinoma

Small cell carcinoma expressed 87,204

Non-smallcellcarcinoma over-expressed and higher in late stages 171, 205

Adenoma & squamous over-expressed 84,85, 170, cell carcinoma higher expression in metastatic cases 206

Lymphoma over-expressed 82

Burkitt's lymphoma over-expressed 80,82

Hodgkin's disease over-expressed 80

Plasma cell expressed 180

Melanoma over-expressed; higher in metastatic cases 88,207,208

Mesothelioma highly expressed 85

Table 3. continuing

Type of tumour

Expression of Met receptor

References

Myeloma

over-expressed

163, 178

expressed

180

Ovarian cancer

over-expressed

97, 98

Pancreatic cancer

over-expression

100, 102

over-expressed but lower in invasive tumour

174

expressed

99

Peripheral nerve sheath

expressed

177

tumour

Prostate cancer

over-expressed; higher in metastatic tumour

104, 105, 109,

209

Renal cell carcinoma

over-expressed

108

higher in metastatic cases

109,210

Thyroid cancer

low or negative expression

211

expressed and higher in advanced cancers

212,213

highly expressed in papillary carcinoma

214

Figure 7. Invasion of human gallbladder cancer cells in co-culture with stromal fibroblasts and inhibition by anti-HGF antibody. Human gallbladder cancer cells were cultured alone 011 collagen gel or co-cultured with stromal fibroblasts embedded in the gel. Tumour cells did not invade the gel in the absence of fibroblasts yet did invade the gel in co-culture with fibroblasts. The invasion of tumour cells in the co-culture was almost completely inhibited by anti-HGF antibody.

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