Metabotropic glutamate receptors (mGlus) and cellular transformation

Abstract

Although the glutamatergic system usually functions in the CNS, expression has been observed in non-neuronal tissues and a subset of cancers. Metabotropic glutamate receptors (mGlus) are highly "druggable" GPCRs and thus a priority for validation as therapeutic targets. We have previously reported that the aberrant expression of mGlu1 is sufficient to induce spontaneous melanoma development in vivo. We isolated and characterized several stable mGlu1-mouse melanocytic clones and demonstrated that these clones are transformed and tumorigenic. We hypothesize that expression of mGlus may not be uncommon in the pathogenesis of tumors other than melanoma, and that activity of an otherwise normal glutamate receptor in an ectopic cellular environment involves signaling pathways which dysregulate cell growth, ultimately leading to tumorigenesis. As most human cancers are of epithelial origin (carcinomas), in this review, the possibility that mGlu1 could function as a complete oncogene and transform epithelial cells is also discussed.

Figure 1

Spontaneously immortalized melanocytes, melan-a, were transfected with empty vector or Grm1 cDNA. Stable clones expressing mGluR1 were selected with neomycin. Western immunoblots showed various levels of mGluR1 expression among these clones at ~150kD. Allografts of these mGluR1 stable clones into both immunodeficient nude (A) and immunocompetent syngeneic (B) mice showed aggressive tumor formation. 10⁶ cells of each mGluR1 clone and vector control were inoculated subcutaneously. Visible lesions of mGluR1 stable clones in nude mice were detected approximately after 3–5 days of inoculation and the size of tumors reached 600 mm³ after 15 days. In contrast, vector control clones formed no tumor even after 4 weeks of inoculation. All mGluR1 allografted mice were sacrificed after 4 weeks due to the tumor burden.

Figure 1

Spontaneously immortalized melanocytes, melan-a, were transfected with empty vector or Grm1 cDNA. Stable clones expressing mGluR1 were selected with neomycin. Western immunoblots showed various levels of mGluR1 expression among these clones at ~150kD. Allografts of these mGluR1 stable clones into both immunodeficient nude (A) and immunocompetent syngeneic (B) mice showed aggressive tumor formation. 10⁶ cells of each mGluR1 clone and vector control were inoculated subcutaneously. Visible lesions of mGluR1 stable clones in nude mice were detected approximately after 3–5 days of inoculation and the size of tumors reached 600 mm³ after 15 days. In contrast, vector control clones formed no tumor even after 4 weeks of inoculation. All mGluR1 allografted mice were sacrificed after 4 weeks due to the tumor burden.

Figure 2

mGluR1 stable clones showed malignant phenotype in nude mice. (A) Formation of new blood vessels (angiogenesis). mGluR1 stable clones showed strong angiogenic activities. An example of angiogenesis from mGluR1 clone 20 and 29 tumors is shown. (B) Invasion of MASS clones was detected in muscle (top picture) and intestine (bottom picture) after 2 weeks and 4 weeks, respectively.

Figure 2

mGluR1 stable clones showed malignant phenotype in nude mice. (A) Formation of new blood vessels (angiogenesis). mGluR1 stable clones showed strong angiogenic activities. An example of angiogenesis from mGluR1 clone 20 and 29 tumors is shown. (B) Invasion of MASS clones was detected in muscle (top picture) and intestine (bottom picture) after 2 weeks and 4 weeks, respectively.