Theresa P. Pretlow, Ph.D.

Professor, Emeritus

Mailing Address:
2103 Cornell Rd.
WRB 5120
Cleveland, OH 44106-7288

phone: (216) 368-8702
fax: (216) 368-0494

Theresa P. Pretlow received her Ph.D. from the Department of Radiation Biology at the University of Rochester School of Medicine and Dentistry in 1966. After a brief postdoctoral fellowship in the Department of Bacteriology at the University of Wisconsin, Madison, WI, she devoted herself full-time to home and a family of three boys for seven years. She did a second postdoctoral fellowship (part-time) in the Department of Pathology at the University of Alabama in Birmingham (UAB) from 1974-1977 and a sabbatical at Max Planck Institute in Munich and Stanford University from 1977-1978. She became an instructor of Pathology at UAB in 1978 and a Research Assistant Professor of Pathology (part-time) from 1979-83. From 1983-1984, she was a Visiting Lecturer in Medicine at Harvard Medical School. She joined CWRU as Assistant Professor from 1983-1989, as Associate Professor from 1989-1996 and as Professor from 1996-present. She holds secondary appointments in the Department of General Medical Sciences (Oncology) and Environmental Health Sciences. She has been a member of several grant review panels for NIH, the Department of Defense, and the American Cancer Society; was an associate editor of Cancer Research; has served as Secretary of Women in Cancer Research (1995-1998) as President-elect, President, and Past-President of the Histochemical Society (1995-1998), and as a program committee member of the American Society for Investigative Pathology (2003-2006). Currently she is a member of several professional societies and is an associate editor for the Journal of Histochemistry and Cytochemistry.

Dr Theresa Pretlow is interested in the development of cancer, i.e., the changes that take place during the transformation of normal cells to malignant ones. Aberrant crypt foci (ACF) are lesions that were first identified microscopically in unembedded colons from rodents as soon as 2 weeks after a single dose of carcinogen. Her laboratory was the first to report these lesions in the macroscopically normal colonic mucosa of humans. The frequency of these lesions is increased in patients with colon cancers compared to those without colon cancer and in patients with hereditary conditions such as familial adenomatous polyposis (FAP) compared with patients with sporadic colon cancer. This not only validated the animal model, but it provided identifiable lesions to characterize the early events that precede colon cancer in humans. Mutations in codon 12 of K-ras were found in 11 (73%) of 15 ACF but not in any of 27 morphologically normal crypt areas from the same patients. The hypothesis that ACF are precursors of human colon cancer is further strengthened by her demonstration of (a) microsatellite instability and (b) the expression of antigens associated with colonic neoplasia such as sialyl Tn and sialyl LewisX antigens, fragile histidine triad (Fhit) protein, inducible nitric oxide synthase, telomerase, beta-catenin, c-myc, and Apc in subpopulations of human aberrant crypt foci. The increased expression of immunohistochemically demonstrable carcinoembryonic antigen (CEA) was found to be an excellent marker for paraffin-embedded sections of human ACF. This allowed the demonstration of dysplasia in 27 of 50 (54%) of human ACF. The demonstration of monoclonality in ACF either lacking dysplasia or with mild dysplasia makes ACF the earliest identifiable neoplastic lesions in human colon. Recent studies have demonstrated hypermethylation of several genes in ACF indicating that inactivation of genes by methylation often occurs very early in the neoplastic process. Methylation of secreted frizzle-related protein (SFRP) genes SFRP1 in 93% and SFRP2 in 87% of ACF allows constitutive Wnt signaling in these putative colorectal cancer precursors that generally lack APC mutations. The finding of abnormal DNA fingerprints and the loss of heterozygosity (LOH) of tumor suppressor genes suggest chromosomal instability (CIN) can occur early in colon neoplasia, even before APC mutations. Our future studies shall continue to explore (a) genetic, epigenetic and phenotypic alterations that characterize these earliest neoplastic lesions of the colon, and (b) how ACF can be used in vivo to decrease the current high morbidity and mortality associated with colon cancer.

Siu I-M, Robinson DR, Schwartz S, Kung H-J, Pretlow TG, Petersen RB, Pretlow TP (1999). The identification of monoclonality in human aberrant crypt foci. Cancer Res 59, 63-66.

Boivin GP, Washington K, Yang K, Ward JM, Pretlow TP, Russell R, Besselsen DG, Godfrey VL, Doetschman T, Dove WF, Pitot HC, Halberg RB, Itzkowitz SH, Groden J, Coffey RJ (2003). Pathology of mouse models of intestinal cancer: Consensus report and recommendations. Gastroenterology 124: 762-777, 2003

Li H, Myeroff L, Smiraglia D, Romero MF, Pretlow TP, Kasturi L, Lutterbaugh J, Rerko R, Casey G, Issa J- P, Willis J, Willson JKV, Plass C, Markowitz SD (2003). SLC5A8: A sodium transporter, is a tumor suppressor gene silenced by methylation in human colon aberrant crypt foci and cancers. Proc Natl Acad Sci USA 100: 8412-8417.

Luo L, Li B, Pretlow TP (2003). DNA alterations in human aberrant crypt foci and colon cancers by random primed polymerase chain reaction (PCR). Cancer Res 63: 6166-6169.

Suzuki H, Watkins DN, Jair K-W, Schuebel KE, Markowitz SD, Chen W-D, Pretlow TP, Yang B, Akiyama Y, Engeland Mv, Toyota M, Tokino T, Hinoda Y, Imai K, Herman JG, Baylin SB(2004). Epigenetic inactivation of SFRP genes allows constitutive Wnt signaling in colorectal cancer. Nat Genet 36: 417-422.

Luo L, Chen W-d, Pretlow TP (2005). CpG island methylation in aberrant crypt foci and cancers from the same patients. Int J Cancer 115: 747-751.

Chen WD, Han ZJ, Skoletsky J, Olson J, Sah J, Myeroff L, Platzer P, Lu S, Dawson D, Willis J, Pretlow TP, Lutterbaugh J, Kasturi L, Willson JK, Rao JS, Shuber A, Markowitz SD (2005). Detection in fecal DNA of colon cancer-specific methylation of the nonexpressed vimentin gene. J Natl Cancer Inst 97: 1124- 1132, 2005.