A major focus of research in the Rittling lab is understanding the interaction of tumor and surrounding normal cells during the processes of tumor development and metastasis. It is clear that tumors develop surrounded by normal cells ("host cells") of various types, including immune cells, blood vessels and normal tissue cells. It has become more and more clear that these normal cells contribute to the process of tumor development, and we are working to understand this interaction. The interaction is especially clear in the development of bone metastases, a common complication of breast, prostate and lung cancer. Tumor cells that escape from the original cancer migrate to the bone where they grow and frequently cause bone destruction.
The cells that are responsible for the destruction of the bone, osteoclasts, are normal bone cells that are hyperactivated by the tumor. We seek to understand the mechanism by which this hyperactivation happens, and also to ask what are the special conditions in the bone that favor tumor growth. We have developed a unique mouse breast cancer cell line that forms bone metastasis efficiently and can use these cells to form tumors in genetically modified mice to understand the role of different mouse genes in the host response to the tumor. Some of the genes of interest are those coding for secreted proteins such as TGFb, CSF-1 and PTHrP. Recently, we discovered that this breast cancer cell line forms metastases in the eye, providing a novel mouse model for a complication found in human breast cancer patients.
Another area of interest is the role of stem cells in the development of tumors and metastases. Using a model of chemically-induced breast cancer in the mice, we observed development of a wide range of tumor types. We hypothesize that this variety occurs because the tumors arise from stem cells that have the ability to change into different breast cell types as the tumor develops. A project funded by the Department of Defense is underway to test this idea.
Finally we maintain a long-term interest in the role of the protein osteopontin in normal and diseased tissues. This protein is abundant in bone, but its appearance in immune and other soft tissue cells suggested a broader role in the body. Some time ago, we developed a mouse unable to make osteopontin (OPN knockout mouse) and these mice have been used in laboratories around the world to understand the role of OPN in bone resorption, regulation of the immune system, vascular disease and other diseases. OPN also is strongly associated with tumor development and metastasis—in many different human tumor types, patients with tumors that express high levels of OPN have a poorer prognosis than those with low levels. We are interested in the mechanism of action of OPN in promoting tumor growth, comparing the tumorigenic and metastatic properties of OPN-deficient and normal tumor cells in mice. We are also studying the structure-function relationships of this protein, as well as its special relationship to bone loss under pathological conditions.
Borges K, Gearing M, Rittling S, Sorensen ES, Kotloski R, Dehnardt DT, Dingledine R. 2008 Characterization of osteopontin expression and function after status epilepticus. Epilepsia. 49(10):1675-85.
Ono N, Nakashima K, Rittling SR, Schipani E, Hayata T, Soma K, Denhardt DT, Kronenberg HM, Ezura Y, Noda M. 2008 Osteopontin Negatively Regulates Parathyroid Hormone Receptor Signaling in Osteoblasts. J Biol Chem. 283(28):19400-19409.
Yates B, Zetterberg C, Rajeev V, Reiss M, Rittling SR. 2007 Promoter-independent regulation of vimentin expression in mammary epithelial cells by val(12)ra: and TGFbeta. Exp Cell Res. 313(17):3718-28.
Ramaiah SK, Rittling S. 2007 Role of osteopontin in regulating hepatic inflammatory responses and toxic liver injury. Expert Opin Drug Metab Toxicol. 3(4):519-26.
Koyama Y, Rittling SR, Tsuji K, Hino K, Salincarnboriboon R, Yano T, Taketani Y, Nifuji A, Denhardt DT, Noda M. 2006 Osteopontin deficiency suppresses high phosphate load-induced bone loss via specific modulation of osteoclasts. Endocrinology.147(6):3040-9.
Lorena D, Darby IA, Gadeau AP, Laetitia Lam Shang Leen L, Rittling S, Porto LC, Rosenbaum J, Desmouliere A. 2006. Osteopontin expression in normal and fibrotic liver. Altered liver healing in osteopontin-deficient mice. J. Hepatol. 44(2) :383-390.
Maeno Y, Nakazawa S, Yamamoto N, Shinzato M, Nagashima S, Tanaka K, Sasaki J, Rittling SR, Denhardt DT, Uede T, Taniguchi K. 2006. Osteopontin participates in Th1 -mediated host resistance against nonlethal malaria parasite Plasmodium chabaudi chabaudi infection in mice. Infect. Immun. 74(4) :2423-2427.
Lai CF, Seshadri V, Huang K, Shao JS, Cai J, Vattikuti R, Schumacher A, Loewy AP, Denhardt DT, Rittling SR, Towler DA. 2006. An osteopontin-NADPH oxidase signaling cascade promtes pro-matrix metallo-proteinase 9 activation in aortic mesenchymal cells. Circ. Res. 98 (1 2)1479-1489.
Ge R, Rajeev V, Ray P, Lattime E, Rittling S, Medicherla S, Protter A, Murphy A, Chakravarty J, Dugar S, Schreiner G, Barnard N, Reiss M. (2006) Inhibition of growth and metastasis of mouse mammary carcinoma by selective inhibitor of transforming growth factor-beta type 1 receptor kinase in vivo. Clin. Cancer Res. 12(14 Pt. 1):4315-4330.
Kuhn M, Shah S, Natasha T, Rittling SR. 2006. A mouse model of breast cancer metastasis to the choroid of the eye. Clin Exp. Metastasis 22(8):685-90
da Silva AP, Pollett A, Rittling SR, Denhardt DT, Sodek J, Zobar R. 2006. Exacerbated tissue destruction in DSS-induced acute colitis of OPN-null mice is associated with downregulation of TNF-alpha expression and non-programmed cell death. J. Cell Physiol. 208 (3):629- 639
Natasha T, Kuhn M, Kelly O, Rittling SR. 2006. Override of the osteoclast defect in osteopontin-deficient mice by metastatic tumor growth in the bone. Am. J. Pathol. 168 (2) :551–561.
Vernon HJ, Osborne C, Tzortzaki EG, Yang M, Chen J, Rittling SR, Denhardt DT, Buyske S, Bledsoe SB, Evan AP, Fairbanks L, Simmonds HA, Tischfield JA, Sahota A. 2005. Aprt/Opn double knockout mice: Osteopontin is a modifier of kidney stone disease severity. Kidney Int. 68(3):938–947.
Stier S, Ko Y, Forkert R, Lutz C, Neuhaus T, Grunewald E, Cheng T, Dombkowski D, Calvi LM, Rittling SR, Scadden DT. 2005. Osteopontin is a hematopoietic stem cell niche component that negatively regulates stem cell pool size. J. Exp. Med. 201(11):781–791.
Diao H, Kon S, Iwabuchi K, Morimoto J, Ito D, Segawa T, Maeda M, Hamuro J, Yagita H, Van Kaer L, Onoe K, Denhardt D, Rittling S, Uede T. 2004. Natural killer T cell-derived osteopontin induces hepaptocellular injury in concanavalin A-induced fulminant hepatitis. Immunity 21 (4):539–550.
Rittling SR, Chambers AF. 2004. Role of osteopontin in tumor progression. Br. J. Cancer 90(10):1877–1881.
Bourassa B, Monaghan S, Rittling SR. 2004. Reduced cytotoxicity of OPN-deficient peritoneal macrophages. Cell Immunol. 227(1):1–11.
Chen Y-P, Rittling, SR. 2003. Novel murine mammary epithelial cell lines that form osteolytic bone metastases: Effect of strain background on tumor homing. Clin. Exp. Metastasis 20(1):111–120.