The role of
1.1. General properties and functions of METCAM/MUC18
It is now well documented that although tissue specific signatures exist in different cancer types, cancers from different tissues also express some common genes [10-12]. One group of them is cell adhesion molecules (
mediating the remodeling of cytoskeleton . They also actively mediate the cell-to-cell and cell-to-extracellular matrix interactions to allow cells to constantly respond to physiological fluctuations and to alter/remodel the surrounding microenvironment for survival . They do so by crosstalk with cellular surface growth factor receptors, which interact with growth factors that may be secreted from stromal cells or released from circulation and embedded in the extracellular matrix [13-14]. Thus an altered expression of
However, METCAM enables both human and mouse melanoma cells to metastasize only under an experimental metastasis assay (tail vein injection), not under a spontaneous metastasis assay (subcutaneous injection). In addition, the ectopic expression of METCAM in METCAM-minus melanoma cell lines has no effect or a slight suppressive effect on the tumorigenesis. Taken together, this suggests that METCAM promotes the metastasis of melanoma cells only at later stages of progression (it has been found that fibroblast growth factor-2 initiates the metastatic process) .
Recently, we further investigated the effect of moMETCAM expression on tumorigenesis and metastasis of a different mouse melanoma subline #9 of K1735 (K1735-9 or K9), which is also METCAM-minus and lowly metastatic, but has a highly tumorigenic phenotype (tumor+++/metlow), in the syngeneic C3H mouse model. We tested the effect of ectopic expression of moMETCAM on
We suggest that METCAM-mediated tumorigenesis and metastasis of melanoma cells and other cancer cells is dependent on intrinsic co-factors of different K1735 sublines and cancer types. The establishment of an immune-competent syngeneic mouse model for the METCAM-mediated progression is physiologically more relevant to and should provide knowledge more applicable to clinical melanoma than immune-deficient xenograft mouse models. The putative mechanisms of METCAM-mediated promotion/suppression of melanoma progression will also be discussed.
2. Metcam and melanoma tumorigenesis
Only one group showed that over-expression of
The most convincing evidence for its tumor suppressor effect is in the subline #9 of the mouse melanoma cell line
3. Metcam and melanoma metastasis
METCAM increases the progression of most melanoma cell lines with the exception of one mouse melanoma subline, K1735-9. We found over-expression of
Table 1 summarizes the possible role of
|Clinical melanoma and human melanoma cell lines||No effect||Increasing (effect is in the late stages)||3, 17|
|Mouse melanoma K1735 sublines #3 and #10||No effect or slight suppression||Increasing (effect is in the late stages)||9, 18|
|Mouse melanoma K1735 subline #9||Suppression||Suppression||20, 21|
As shown in Table 1,
4. Mechanisms of metcam-mediated melanoma progression
First, the transcriptional expression of
Second, since the cytoplasmic tail of
Third, after the engagement of
Fourth, from what we know about the roles of other
Eighth, malignant progression of cancer cells has been shown to associate with abnormal glycosylation, resulting in expression of altered carbohydrate determinants . Thus, the glycosylated status of
We should always keep in mind that the mechanisms of
5. Conclusion and clinical applications
I thank Mr. Jonathan C. – Y. Wu for critical reading of the manuscript and proof reading of the English.
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