Ectopic expression of MCAM/MUC18 increases in vitro motility and invasiveness, but decreases in vivo tumorigenesis and metastasis of a mouse melanoma K1735-9 subline in a syngeneic mouse model

Abstract

Ectopic expression of MCAM/MUC18, a cell adhesion molecule in the immunoglobulin-like gene superfamily, induces two moMCAM/MUC18-minus, non-metastatic mouse melanoma K1735 sublines, K3 (tumor/met) and K10 (tumor/met), to metastasize to lungs in a syngeneic C3H mouse model. In this report, we extended investigation of effects of moMCAM/MUC18 expression on tumorigenesis and metastasis in another lowly metastatic, however highly tumorigenic moMCAM/MUC18-minus mouse melanoma K1735 subline, K9 (tumor/met). We transfected this subline with the moMCAM/MUC18 cDNA, selected for G418-resistant clones with different expression levels of moMCAM/MUC18, and used them for testing effects of MCAM/MUC18 expression on in vitro growth rate, motility, and invasiveness, in vivo subcutaneous tumor growth, and pulmonary metastasis in syngeneic C3H brown mice. Similar to K3 and K10 cells, increased expression of MCAM/MUC18 in K9 cells did not significantly affect in vitro growth rate, but increased in vitro motility and invasiveness. Surprisingly, increased expression of MCAM/MUC18 in K9 cells decreased their induction of tumorigenesis and suppressed their establishment of pulmonary nodules in syngeneic C3H brown mice. We concluded that increased MCAM/MUC18 expression in K9 subline increased in vitro epithelial-to-mesenchymal transition; however, it suppressed in vivo tumorigenicity and metastasis. Thus MCAM/MUC18 acts as a tumor and metastasis suppressor for the K9 subline, different from its role in other K1735 sublines, K3 and K10. Different intrinsic co-factors in different K1735 sublines, which modulate the functions of MCAM/MUC18 in the cells that interact differently to the tumor microenvironment, may render sublines manifest differently in tumorigenicity and metastasis in vivo.

METCAM/MUC18: A Novel Tumor Suppressor for Some Cancers

“…In contrast, over-expression of moMETCAM/MUC18 in K1735-3 and K1735-10 subline has an opposite effect (namely promotion) on lung nodule formation. In conclusion, moMETCAM/MUC18 acts as a tumor suppressor with a different severity on different cell lines in a syngenetic mouse model [21,22].…”

“…In contrast, over-expression of METCAM/MUC18 represses tumorigenesis of a mouse melanoma cell line, K1735-9 [22], nasopharyngeal carcinoma type I [24,25] and perhaps hemangiomas [46]. METCAM/MUC18 over-expression also represses the distant organ-dissemination of the mouse melanoma cell line, K1735-9 [22].…”

“…Over-expression of moMETCAM/MUC18 in one mouse melanoma cell line K1735 clone 10 (or K1735-10 subline) has no effect and that in another cell line K1735 clone 3 a slight suppression effect on subcutaneous tumorigenesis [21], but in K1735 clone 9 (or K1735-9 subline) it completely suppresses the subcutaneous tumorigenesis [22]. Thus, METCAM/MUC18 definitely acts as a tumor suppressor for the K1735-9 subline, but may have a less obvious effect on two other K1735 sublines, K1735-3 and K1735-10.…”

“…Effects of the aberrant expression of the following CAMs on tumorigenesis and malignant progression are better studied, such as cadherin [9], integrins [10], CD44 [11], CEACAM [12], mucins [13], L1CAM [14], EpCAM [15], ALCAM [16] and METCAM/MUC18 [17]. Over the past several years, our team investigated the role of METCAM/MUC18 in several types of tumors, such as melanoma, breast, nasopharyngeal, ovarian and prostate cancers [18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36]. The resulting data showed a dual role of METCAM/MUC18 as a tumor promotor or suppressor in these cancers [17,37].…”

Dual Role of METCAM/MUC18 Expression in the Progression of Cancer Cells

“…This also suggests that many alternative pathways are possible for metastasis, similar to multiple alternative pathways leading to tumorigenesis [2,3]. This includes the genes encoding cell adhesion molecules (CAMs), such as E-cadherin [5], integrins α2β1 [6] and αVβ3 [7], CD44 [8], EPCAM [9,10], ALCAM [11], and METCAM/MUC18 [12,13]. The list of these genes has been rapidly lengthened because of the advent of modern state-of-the-art technologies, such as SAGE analysis [14,15], DNA chip microarray analysis [16][17][18][19], and proteomics [20][21][22].…”