Demonstration of tumor suppression by mannose 6-phosphate/insulin-like growth factor 2 receptor

Abstract

The mannose 6-phosphate/IGF-2 receptor has been proposed to be a tumor suppressor gene on the basis of loss of heterozygosity and mutations in tumors from cancer patients. To test this hypothesis, the receptor was expressed in 66cl4, a mouse mammary tumor cell line deficient in the receptor. Expression of the receptor corrected the abnormal lysosomal trafficking phenotype displayed by these cells. Receptor expression had no apparent effect on growth or invasiveness of the cells in vitro but effectively inhibited formation of mammary tumors in BALB/c mice. Analysis of cell proliferation and apoptosis in tumors indicated that the primary effect of the receptor was to inhibit cell proliferation. Proliferation indices for receptor-deficient and receptor-expressing tumors, as determined by BrdU incorporation, were 24.6 and 7.6%, respectively. No significant effect of receptor expression on apoptosis was observed. Receptor expression similarly inhibited tumor growth in BALB/c scid mice indicating that cytotoxic T cells and other components of the immune system missing in scid mice are not involved in the receptor's tumor suppressing effect. These findings establish a role for the receptor as a bona fide tumor suppressor gene and together with previous studies, suggest an important role for the receptor in human and rodent cancers.

The mannose 6‐phosphate/insulin‐like growth factor II receptor restricts the tumourigenicity and invasiveness of squamous cell carcinoma cells

“…24 In contrast, subnormal levels of ectopically expressed M6P/IGF2R did not affect the motility of receptor-deficient murine mammary tumour cells. 25 In the case of SCC-VII cells, the migratory response of M6P/IGF2R-positive cells was consistently lower than that of their parental counterparts, even though the former displayed near physiological M6P/IGF2R levels. These results indicate that the M6P/IGF2R status affects the ability of squamous cell carcinoma cells to penetrate ECM barriers.…”

“…26 For choriocarcinoma and breast tumour cells, the growth-suppressive capacity of M6P/ IGF2R has been also verified in vivo. [23][24][25] It is thought that the anti-proliferative activity of M6P/IGF2R in tumour cells is mainly due to its impact on IGF-II signalling. 24,44 Wise and Pravtcheva have demonstrated that the presence of an Igf2r transgene delays Igf2-induced mammary tumour formation in mice.…”

“…27,28 However, these studies were all performed using receptor-positive cancer cell lines, with only one of them displaying a reduced M6P/ IGF2R content. 25 Moreover, the impact of M6P/IGF2R on tumour invasion and metastasis is only poorly understood, with controversial results reported for breast cancer cells. 24,25 We have previously shown that M6P/IGF2R-deficient SCC-VII murine squamous cell carcinoma cells secrete large amounts of matrix-degrading cathepsins.…”

The V-ATPase-Inhibitor Archazolid Abrogates Tumor Metastasis via Inhibition of Endocytic Activation of the Rho-GTPase Rac1

“…To this end, we used the 4T1-Luc syngeneic metastatic mouse breast cancer model (24)(25)(26)(27). This model is based on the 4T1-Luc mouse mammary tumor cell line, which when injected intravenously disseminates to distant organs, homing to lungs, liver, bone, and brain over a short period of time.…”

Soluble IGF2 Receptor Rescues Apc Min/+ Intestinal Adenoma Progression Induced by Igf2 Loss of Imprinting

“…We then tested whether the phenotypes observed are due to increased ligand supply by the introduction of a bovine keratin 10-driven transgene expressing a soluble full-length mouse Igf2r (K10DIgf2r), previously shown to act as a ligand trap and to limit IGF-II bioavailability (23,(34)(35)(36)(37).…”