Papilloma Development Is Delayed in Osteopontin-Null Mice: Implicating an Antiapoptosis Role for Osteopontin

Abstract

Osteopontin is a secreted, adhesive glycoprotein, whose expression is markedly elevated in several types of cancer and premalignant lesions, implicating its association with carcinogenesis. To test the hypothesis that induced osteopontin is involved in tumor promotion in vivo, osteopontin-null and wild-type (WT) mice were subjected to a two-stage skin chemical carcinogenesis protocol. Mice were initiated with 7,12-dimethylbenz(a)anthracene (DMBA) applied on to the dorsal skin followed by twice weekly application of 12-Otetradecanoylphorbol-13-acetate (TPA) for 27 weeks. Osteopontin-null mice showed a marked decrease both in tumor/ papilloma incidence and multiplicity compared with WT mice. Osteopontin is minimally expressed in normal epidermis, but on treatment with TPA its expression is highly induced. To determine the possible mechanism(s) by which osteopontin regulates tumor development, we examined cell proliferation and cell survival. Epidermis from osteopontin-null and WT mice treated with TPA thrice or with DMBA followed by TPA for 11 weeks showed a similar increase in epidermal hyperplasia, suggesting that osteopontin does not mediate TPA-induced cell proliferation. Bromodeoxyuridine staining of papillomas and adjacent epidermis showed no difference in cell proliferation between groups. However, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling analyses indicated a greater number of apoptotic cells in DMBA-treated skin and papillomas from osteopontinnull versus WT mice. These studies are the first to show that induction of the matricellular protein osteopontin facilitates DMBA/TPA-induced cutaneous carcinogenesis most likely through prevention of apoptosis.

Osteopontin: Role in immune regulation and stress responses

“…OPN has long been regarded as a survival factor, in part by inhibiting apoptosis induced by a pathological event, growth factor deprivation for example (Khan et al, 2002). It has been demonstrated that OPN is an important anti-apoptotic factor in many circumstances; for example, OPN promotes cancer cell metastasis due to its anti-apoptotic properties that prevent programmed cell death and allows uncontrolled proliferation of tumor cells (Hsieh et al, 2006). OPN has also been found to block the activation-induced cell death of macrophage and T lymphocyte as well as fibroblasts and endothelial cells exposed to harmful stimuli Standal et al, 2004).…”

Interferon-induced transmembrane 3 binds osteopontin in vitro: expressed in vivo IFITM3 reduced OPN expression

“…(Meller et al, 2005). It has also been shown that OPN-deficient mice have higher TUNEL staining and less papilloma development when treated with chemical carcinogen (Hsieh et al, 2006). Furthermore, permanent transfection of IFITM3 antisense cDNA (as-IFITM3) in an expression vector into R37 cells led to an elevated level of OPN mRNA and protein expressions and conferred the ability to increase cell invasion.…”

OPN/CD44v6 overexpression in laryngeal dysplasia and correlation with clinical outcome

“…Taken together, these findings suggest that OPN signalling through CD44v6 may play a role in the establishment of dyplastic changes in the laryngeal epithelium. Interestingly, it has been recently reported that genetic deletion of OPN in transgenic mice did not change the rate of hyperplasia formation but caused a reduction of benign papilloma formation after the two-stage skin chemical carcinogenesis protocol; thus, also in this experimental model system, OPN is involved in the early phases of tumorigenesis (Hsieh et al, 2006).…”