Robert J. Gillies
Professor of Biochemistry, Physiology and Radiology
Ph.D. 1979, University of California, Davis

Web Site: Laboratory Homepage

Tumor Metabolism

Research Interests

The research in my group centers on investigating cancer cell and tumor physiology and metabolism using non-invasive imaging and spectroscopic methods. The results we have obtained are important to the basic mechanisms of carcinogenesis, as well as to cancer diagnosis and treatment. Cancer is often characterized as a genetic disease, since it invariably results from genomic alterations or mutations. However, only 20% of cancers are clearly heritable, meaning that the majority of cancers have environmental triggers. We have shown that the environmental (interstitial) pH of tumors is quite acidic. This was determined using Nuclear Magnetic Resonance Spectroscopy (MRS) of human tumors grown in SCID mice. Using magnetic resonance imaging (MRI) we are determining the relationship between angiogenesis, the metabolism and low pH in tumors. This acidic pH affects therapeutic efficacy and may impact on carcinogenesis itself. A major research project in my lab is focused on improving measurement of acid pH by MRS and defining the impact of acid pH on chemotherapy. Acidic pH makes tumors physiologically resistant to weakly basic chemotherapeutic drugs, such as doxorubicin (adriamycin). Raising the tumor pH reverses this resistance. We have also shown that this acid pH induces tumor cells to become more invasive, which is a hallmark of malignancy. Transfection of metastatic cells with nm23, which inhibits metastasis, has a significant impact on cellular lipid metabolism and cellular pH homeostasis. Changes in lipid metabolism is an important diagnostic marker for cancer progression.

Cell pH is regulated by three distinct families of transporters: Na/H exchange, bicarbonate transport and proton ATPases. A significant number of human tumor cells express Vacuolar-type H(+)-ATPases (V-ATPase) in their plasma membranes. We have cloned one of the subunits of this pump from human cDNA libraries and are using expression clones to raise antibodies against extracellular epitopes of this pump. Research using antibodies which recognize these extracellular epitopes suggests that these ATPases are constantly and rapidly turned over between intracellular organelles and the cell surface. This activity could have a significant effect on resistance of tumor cells to weakly basic chemotherapeutic drugs, such as adriamycin doxorubicin) or mitoxantrone.

Recent Publications

Gillies RJ, Bhujwalla ZM, Evelhoch J, Garwood M, Neeman M, Robinson SP, Sotak, CH and Van Der Sanden B (2000) Applications of Magnetic Resonance in Model Systems: Tumor Biology and Physiology. Neoplasia 2:139-151

Evelhoch JL, Gillies RJ, Karczmar GS, Koutcher JA, Maxwell RJ, Nalcioglu O, Raghunand N, Ronen SM, Ross BD and Swartz HM. (2000) Applications of Magnetic Resonance in Model Systems: Cancer Therapeutics. Neoplasia 2, 152-165.

Pilatus U, Ackerstaff E, Artemov D, Mori N, Gillies RJ and Bhujwalla ZM (2000) Imaging Prostate Cancer Invasion with Multi-Nuclear Magnetic Resonance Methods: The Metabolic Boyden Chamber: Neoplasia 2:273-279

Raghunand N and Gillies RJ (2000) pH and drug resistance in tumors. Drug Resistance Updates 3:39-47

Gillies RJ, Bhujwalla ZM, Stubbs M, Griffiths JM (2001) The Tumor Microenvironment: Causes and Consequences of hypoxia and acidity. Novartis Foundation Symposium 240. RJ Gillies (chair)

Raghunand N, Mahoney B, Van Sluis R, Baggett B, Gillies RJ. (2001) Acute metabolic alkalosis enhances response of C3H mouse mammary tumors to the weak-base mitoxantrone. Neoplasia 3:227-235.

Raghunand N and Gillies RJ (2001) pH and Chemotherapy. Novartis Fdn. Symposium 240: 199-211

Gillies RJ (2001) The Tumour Microenvironment: Causes and Consequences of Hypoxia and Acidity. Novartis Foundation Symposium 240. John Wiley & Sons, Ltd., England.

Gillies RJ (2001) Causes and consequences of hypoxia and acidity in tumors. Trends Mol. Med. 7:47-49

Gillies RJ and Lynch RM (2001) Frontiers in the measurement of pH in vivo. Novartis Fdn. Symp. 240:7-18

Gillies RJ and Raghunand N (2001) Nuclear Magnetic Resonance (NMR) Spectroscopy in the Study of Whole-Animal Metabolism. Encyclopedia of Life Sciences 1-6.

Bhujwalla ZM, Artemov D, Aboagye E, Ackerstaff E, Gillies RJ, Natarajan K and Solaiyappan M (2001) The Physiological Environment in Cancer Vascularization, Invasion and Metastasis. Novartis Fdn. Symp. 240:23-37

Bhujwalla ZM, Artemov D, Ballesteros P, Cerdan S, Gillies RJ and Solaiyappan M. (2002) Combined vascular and extracellular pH imaging of solid tumors. NMR in Biomedicine 15:114-119.

Gillies RJ, Raghunand N, Karczmar G and Bhujwalla ZM (2002) MR Imaging of the tumor microenvironment. J Magn. Reson. Imaging 16:430-450.

Gillies RJ (2002) In vivo Molecular Imaging. J. Cell. Biochem. (suppl) 39: 231-238.

Jennings D, Hatton N, Trouard T, Galons J-P, Guo J, Baggett B, and Gillies RJ (2002) Changes in water mobility measured by diffusion MRI predicts the magnitude of response of prostate cancer xenografts to Taxotere chemotherapy. Neoplasia 4:255-260.

Raghunand N, Howison CM, Zhang S, Sherry AD, Gillies RJ (2003) Renal and Systemic pH Imaging by Contrast-Enhanced MRI. Magn. Reson. Med. 49: 249-257.

Morse DL and Gillies RJ (2003) Choline containing compounds as diagnostic, prognostic and therapeutic response indicators for breast cancer. MRS and MRI in Oncology. N.R. Jagannathan, ed. Jaypee Brothers Medical Publishers, New Delhi (in press)

Schornack PA and Gillies RJ (2003) Contributions of metabolism and H+ diffusion to the acidic pH of tumors. Neoplasia 5: 135-145.

Gillies RJ and Hruby VH (2003) Expression-Driven Reverse Engineering of Targeted Imaging and Therapeutic Agents. Expert Opinion on Therapeutic Targets 7: 137-139.

Contact Information

Mailing:
Dr. Robert J. Gillies, Professor
Department of Biochemistry & Molecular Biophysics
University of Arizona
Arizona Cancer Center
1515 N. Campbell #0985
Tucson AZ 85724

Telephone: 520-626-5050, -5052
Fax: 520-621-5051

gillies@u.arizona.edu

Biological Sciences West
1041 East Lowell Street
P.O. Box 210088 · Tucson, AZ 85721-0088
Tel: (520) 621-5110
FAX (520) 626-9204

Life Sciences South
1007 East Lowell Street
P.O. Box 210106 · Tucson, AZ 85721-0106
FAX (520) 621-3709