Nancy Cho, MD; Instructor in Surgery, Harvard Medical School

Boston, MA

Current Site Of Practice: Brigham and Women's Hospital
Hospital Affiliation: Brigham and Women's Hospital
Focus of Research: Desmoid tumor biology
Fellowship Year: 2013 – 2014
Attended: Harvard Medical School

Contact Nancy Cho

Publications

Estrogen receptor α or β loss in the colon of Min/+ mice promotes crypt expansion and impairs TGFβ and HNF3β signaling

Co-Authors Hasson R, Briggs A, Carothers A, Davids J, Wang J, Bertagnolli M

Adenomatous polyposis coli (APC)-regulated Wnt and transforming growth factor-β (TGFβ) signaling cooperate in the intestine to maintain normal enterocyte functions. Human clinical trials showed that estrogen [17β-estradiol (E2)], the ligand of nuclear receptors estrogen receptor α (ERα) and ERβ, inhibited colorectal cancer (CRC) in women. Consistent with this finding, we reported that E2, ERα and ERβ suppressed intestinal tumorigenesis in the C57BL/6J-Min/+ (Min/+) mouse, a CRC model. Here, we extended our results with further comparisons of colon and small intestine from intact female Apc (+/+) (WT), Min/+ and ER-deficient Min/+ mice. In the colon of ER-deficient Min/+ mice, ER loss reduced TGFβ signaling in crypt base cells as evidenced by minimal expression of the effectors Smad 2, 3 and 4 in these strains. We also found reduced expression of Indian hedgehog (Ihh), bone morphogenetic protein 4 and hepatocyte nuclear factor 3β or FoxA2, factors needed for paracrine signaling between enterocytes and mesenchyme. In proximal colon, ER loss produced a >10-fold increased incidence of crypt fission, a marker for wound healing and tumor promotion. These data, combined with our previous work detailing the specific roles of E2, ERα and ERβ in the colon, suggest that ER activity helps to maintain the intestinal stem cell (ISC) microenvironment by modulating epithelial-stromal crosstalk in ways that regulate cytokine, Wnt and Ihh availability in the extracellular matrix (ECM). 

Carcinogenesis. 2014 Jan;35(1):96-102

Immunohistochemical and molecular analysis of tyrosine kinase activity in desmoid tumors

Co-Authors Cho NL, Carothers AM, Rizvi H, Hasson RM, Redston M, Bertagnolli MM

BACKGROUND: Optimal surgical and medical therapy for the treatment of desmoid tumors (DT) is still undefined. Partial response to tyrosine kinase inhibitors (TKI) has previously been described. Here, we examined the role of the tyrosine kinases c-Src and c-Kit in driving desmoid tumorigenesis.

METHODS: Six consecutive DT and matched normal tissues were collected from the operating room. Tissues were embedded in paraffin for immunohistochemical analysis, and protein lysates were prepared for immunoblot and immunoprecipitation.

RESULTS: We found increased levels of β-catenin in five of six (83%) DT relative to matched normal tissue by immunoblot analysis. By immunohistochemistry, β-catenin expression was also increased in DT and localized to the nucleus. In contrast, we observed variable levels of total and activated c-Src and c-Kit expression in DT compared with normal tissue. Finally, β-catenin tyrosine phosphorylation (p-Y) among tumors was variably increased, despite the increased amount of total β-catenin in tumors.

CONCLUSIONS: Our results suggest that c-Src and c-Kit activity in DT is variable, consistent with the heterogeneous nature of this disease. Clinical response to TKI in DT may be via alternative mechanisms unrelated to c-Src or c-Kit activity. Further insight into DT biology will help identify novel drug regimens to limit the morbidity and mortality associated with this disease.

J Surg Res. 2012 Apr;173(2):320-6

Mesenchymal stromal cell mutations and wound healing contribute to the etiology of desmoid tumors

Co-Authors Carothers AM, Rizvi H, Hasson RM, Heit YI, Davids JS, Bertagnolli MM, Cho NL

Desmoid tumors are nonmalignant neoplasms of mesenchymal origin that mainly contain fibroblast lineage cells. These tumors often occur in patients with familial adenomatous polyposis (FAP) coli who have germ line mutations in the APC gene. Given emerging data that has implicated multipotent mesencyhmal stromal cells (MSC) in the origin of mesenchymal tumors, we hypothesized that desmoid tumors may arise in patients with FAP after MSCs acquire somatic mutations during the proliferative phase of wound healing. To test this idea, we examined 16 desmoid tumors from FAP-associated and sporadic cases, finding that all 16 of 16 tumors expressed stem cell markers, whereas matching normal stromal tissues were uniformly negative. Desmoid tumors also contained a subclass of fibrocytes linked to wound healing, angiogenesis, and fibrosis. Using an MSC cell line derived from an FAP-associated desmoid tumor, we confirmed an expected loss in the expression of adenomatous polyposis coli (APC) and the transcriptional repressor BMI-1 while documenting the coexpression of markers for chondrocytes, adipocytes, and osteocytes. Together, our findings argue that desmoid tumors result from the growth of MSCs in a wound healing setting that is associated with deregulated Wnt signaling due to APC loss. The differentiation potential of these MSCs combined with expression of BMI-1, a transcriptional repressor downstream of Hedgehog and Notch signaling, suggests that desmoid tumors may respond to therapies targeting these pathways.

Cancer Res. 2012 Jan 1;72(1):346-55