Osteopontin stimulates preneoplastic cellular proliferation through activation of the MAPK pathway

• Published in: Molecular cancer research Vol. 9; no. 8; pp. 1018 - 1029
• Main Authors: Luo, Xianmin, Ruhland, Megan K, Pazolli, Ermira, Lind, Anne C, Stewart, Sheila A
• Format: Journal Article
• Language: English
• Published: United States 01-08-2011
• Subjects: Carcinoma, Squamous Cell - metabolism; Carcinoma, Squamous Cell - pathology; Cell Cycle Checkpoints - genetics; Cell Line; Cell Proliferation; Cell Transformation, Neoplastic - metabolism; Cell Transformation, Neoplastic - pathology; Cellular Senescence - genetics; Cyclin-Dependent Kinase Inhibitor p16; Cyclin-Dependent Kinase Inhibitor p21 - genetics; Cyclin-Dependent Kinase Inhibitor p21 - metabolism; Fibroblasts - cytology; Fibroblasts - metabolism; Humans; Keratinocytes - cytology; Keratosis - metabolism; Mitogen-Activated Protein Kinase Kinases - metabolism; Mutation; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; Osteopontin - genetics; Osteopontin - metabolism; Precancerous Conditions - metabolism; Precancerous Conditions - pathology; Skin Neoplasms - metabolism; Skin Neoplasms - pathology
• ISSN: 1541-7786; 1557-3125
• DOI: 10.1158/1541-7786.mcr-10-0472

Alterations in the microenvironment collaborate with cell autonomous mutations during the transformation process. Indeed, cancer-associated fibroblasts and senescent fibroblasts stimulate tumorigenesis in xenograft models. Because senescent fibroblasts accumulate with age, these findings suggest that they contribute to age-related increases in tumorigenesis. Previously we showed that senescence-associated stromal-derived osteopontin contributes to preneoplastic cell growth in vitro and in xenografts, suggesting that it impacts neoplastic progression. Analysis of fibroblasts within premalignant and malignant skin lesions ranging from solar/actinic keratosis to squamous cell carcinoma revealed they express osteopontin. Given the stromal expression of osteopontin, we investigated how osteopontin impacts preneoplastic cell growth. We show that osteopontin promotes preneoplastic keratinocyte cellular proliferation and cell survival through the CD44 cell receptor and activation of the MAPK pathway. These data suggest that stromal-derived osteopontin impacts tumorigenesis by stimulating preneoplastic cell proliferation thus allowing expansion of initiated cells in early lesions.