Carcinogenesis and invasionmetastasis via activation of Met receptor

Ligand-dependent constitutive activation of receptor tyrosine kinases through establishment of an autocrine loop in growth factors and their receptors has been found to associate with tumourigenic transformation of cells in in Met/HGF receptor found in patients with (149, 150). These Met/HGF receptor mutations id thus are likely to play a determinant role for many types of cells. Earlier studies showed that stable expression of HGF or the Met receptor gene in distinct types of non-transformed cells confers tumourigenic potential in these cells. Since the Met receptor is predominantly expressed in epithelial but not in mesenchymal cells, while HGF is expressed in mesenchymal but not in epithelial cells, two distinct types of gene transfer experiments were considerable to establish the autocrine loop of the HGF-Met receptor: Expression of HGF in Metpositive (but HGF-negative) epithelial cells, or expression of Met receptor in HGF-positive (but Met-negative) mesenchymal cells. When the HGF gene was stably expressed in a murine hepatic epithelial cell line, the cells showed a scattered phenotype, were capable of growing in soft agar and were tumourigenic in nude mice (152). Similarly, transfection of HGF in non-parenchymal liver epithelial cells resulted in establishment of the HGF-Met autocrine loop, and importantly, these cells exhibited invasive behavior and metastasized to the lung in nude mice (153). On the other hand, stable expression of the Met receptor gene in NIH 3T3 fibroblasts conferred tumourigenic and invasive characteristics in nude mice (154-156). Similarly, expression of the Met receptor gene in mouse 127 cells and human leiomyosarcoma cells resulted in establishment of the HGF-Met autocrine loop and concomitant progression from non-tumourigenic to tumourigenic, invasive and metastatic cancers in nude mice (157). These results indicate that autocrine activation of the Met receptor confers tumourigenic, invasive and metastatic behavior in cancer cells.

Consistent with acquisition of malignant characteristics in cancer cells through experimental establishment of the HGF-Met autocrine loop, transgenic overexpression of the HGF gene in various tissues from early embryonic development in mice was found to be associated with aberrant development and tumourigenesis in several tissues and cells, including melanocytes, hepatocytes, and mammary gland epithelial cells (158-160). Melanomas in the HGF-transgenic mice were metastatic. It should be emphasized, however, that in the other transgenic mice in which the transgene of HGF was expressed in hepatocytes under control of the albumin enhancer/promoter, hepatocarcinogenesis caused by transgenic over-expression of myc gene was suppressed (161). Moreover, hepatocarcinogenesis promoted by phenobarbital was also strongly inhibited by transgenic expression of HGF in the liver (162). Although an explanation for the discrepancy in tumourigenicity has yet to be determined, in the former transgenic mice, HGF was expressed in many kind of tissues and the expression level was extremely high from embryonic to adult stages. Perhaps fractions of precursor cell (stem-like cell) populations might be aberrantly expanded in several tissues, resulting in a greater susceptibility to malignant transformation. On the other hand, inhibition of hepatocarcinogenesis in the latter transgenic mice may be related to growth inhibitory effects of HGF on hepatocellular carcinoma cells (42, 43) and HGF may possibly function as a tumour suppressor during early stages of liver carcinogenesis.

Tumourigenesis and metastatic progression in cells with the activated Met receptor via experimentally introduced HGF-Met autocrine loop suggest the existence of the HGF-Met autocrine loop in naturally developed cancers and tumour cell lines. There are several reports of autocrine activation of the Met receptor in several types of tumour cell lines, including human myeloma (163), human osteosarcoma (164), human glioma (69, 165, 166), human small cell lung carcinoma (87), and mouse mammary carcinoma (167). In these cancer cell lines, HGF affects tumour growth and confers more motile and invasive characteristics, in an autocrine manner.

Table 2 summarizes the co-expression of HGF and Met receptor in tumours, as detected by histological analysis (immunohistochemical analysis in many cases, and in situ hybridization analysis in

Table 2. Co-expression of HGF and Met receptor in cancers.

Type of tumour

Expression pattern

Refs

Breast carcinoma

positive for both HGF and met expression correlates

168,

stronger HGF expression; HGF-positive in stroma

169

Lung adenocarcinoma

Met-positive in all cases; positive for HGF in many cases

85

positive for both HGF and Met

170

Non-small cell lung

over-expression of Met in many cases; over-expression of

171

carcinoma

HGF

Hepatocellular

positive for both HGF and Met in many cases

172

carcinoma

positive for both HGF and Met

173

Pancreatic cancer

Met expression in many cases and some being positive for

174

HGF

Thyroid cancer

positive for both HGF and Met in papillary cases; positive

175

for Met but not for HGF in nonpapillary cases; HGF

expression in stroma

Gliomas

Glioblastoma

positive for both HGF and Met in high incidence

176

Glioma

expression of HGF and Met increases with grade of

73, 166

malignancy

Schwannoma

positive for both HGF and Met in all cases

176

positive for both HGF and Met in many cases; Met

177

Meningioma

expression correlates with malignancy

176

positive for both HGF and Met in high incidence

Multiple myeloma

positive for both HGF and Met; HGF

163

production in primary cultured myeloma;

178

increased HGF leve! in patients

179

Hodgkin lymphoma

positive for both HGF and Met

180

Sarcomas/fibromas

Osteosarcoma

positive for both HGF and Met in some cases, while Met-

181

or HGF-positive in others

positive for HGF; production of HGF

182

Chondrosarcoma

positive for both HGF and Met in some cases, while Met-

181

or HGF-positive in others

Pleural mesothelioma

positive for both HGF and Met

85

Leiomyosarcoma

positive for both HGF and Met in some cases, while Met-

181

or HGF-positive in others

Malignant fibrous

positive for HGF; production of HGF

182

histiocytoma

Neurofibroma

positive for HGF; production of HGF

182

Synovial sarcoma

positive for both HGF and Met in biphasic synovial

183

sarcoma

182

high expression of Met

184

strong Met expression in many of biphasic synovial

sarcoma, but lower in monophasic

184

Epithelioid sarcoma

positive for both HGF and Met

79

Kaposi's sarcoma

positive for both HGF and Met; HGF production by lesion-

derived spindle cells

some cases). Co-expression of HGF and the Met receptor has been detected in many types of tumours, and the incidence of co-expression and their expression pattern varies depending on tumour types. Although most malignant neoplasms (over 90%) are carcinomas (tumours originally derived from epithelial cells), it is noteworthy that co-expression and co-localization of HGF and Met receptor have been noted particularly in sarcomas and hematopoietic tumours, originally derived from mesenchymal cells. Since Met receptor expression is negative or low in mesenchymal or stromal cells in normal tissues (in contrast to expression of HGF in these cells), aberrant induction or activation of Met receptor expression is likely to occur during development of soft tissue and hematopoietic tumours. Likewise, co-expression of HGF and Met was noted in gliomas, in a high incidence, suggesting participation of the HGF-Met autocrine loop in tumourigenesis and malignant progression in these tumours. On the other hand, co-expression of HGF and the Met receptor were noted in several types of carcinoma cells.

Since normal epithelial cells express the Met receptor but not HGF, aberrant activation of the HGF gene in these malignant carcinomas may be involved in carcinogenesis and their malignant progression. Nevertheless, it is noteworthy that the number of carcinomas co-expressing HGF and the Met receptor is relatively low, even though HGF exhibits biological activities for a wide variety of cancer cells and expression and/or overexpression of Met receptor were noted in a wide variety of tumour cells (Table 3). Since HGF is expressed in stromal cells in many types of tumour tissues, paracrine activation of the Met receptor seems to confer malignant characteristics in many cancers, as well as the autocrine activation of Met (see below).

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