Colorectal Adenoma Stem-like Cell Populations: Associations with Adenoma Characteristics and Metachronous Colorectal Neoplasia

Abstract

Cancer stem cells have tumor-initiation and tumor-maintenance capabilities. Stem-like cells are present in colorectal adenomas, but their relationship to adenoma pathology and patient characteristics, including metachronous development of an additional adenoma (“recurrence”), have not been studied extensively. We evaluated the expression of aldehyde dehydrogenase isoform 1A1 (ALDH1A1), a putative stem cell marker, in baseline adenomas from the placebo arm of chemoprevention trial participants with colonoscopic follow-up. An exploratory set of 20 baseline adenomas was analyzed by ALDH1A1 immunohistochemistry with morphometry, and a replication set of 89 adenomas from 76 high-risk participants was evaluated by computerized image analysis. ALDH1A1 labeling indices (ALIs) were similar across patient characteristics and in advanced and non-advanced adenomas. There was a trend toward higher ALIs in adenomas occurring in the right than left colon (p=0.09). ALIs of synchronous adenomas were correlated (intraclass correlation coefficient 0.67). Participants in both sample sets who developed a metachronous adenoma had significantly higher ALIs in their baseline adenoma than participants who remained adenoma-free. In the replication set, the adjusted odds for metachronous adenoma increased 1.46 for each 10% increase in ALIs (p=0.03). A best-fit algorithm-based cut-point of 22.4% had specificity of 75.0% and positive predictive value of 70.0% for metachronous adenoma development. A larger population of ALDH1A1-expressing cells in an adenoma is associated with a higher risk for metachronous adenoma, independent of adenoma size or histopathology. If confirmed, ALDH1A1 has potential as a novel biomarker in risk assessment and as a potential stem-cell target for chemoprevention.

Temporal and spatial changes of cells positive for stem-like markers in different compartments and stages of human colorectal adenoma-carcinoma sequence

“…We have also found that grading scores of LGR5 and ALDH1 positive cells in the cancerous epithelium were significantly increased in CRC patients with advanced TNM stages than those with early stages. Those observations are consist with other groups’ findings [ 15 , 26 – 32 ], and imply that increased stem-like cell density might be the potential predicators for disease stage progression in both the adenoma and CRC. Mesenchymal stem like cell can be observed in the tumor stroma, it plays a critical role in remodeling tumor stroma and forming a supportive environment for cancer growth and metastasis [ 33 ].…”

“…Several potential stem-like markers have been used to identify stem cells in adenomas/CRC. LGR5 and ALDH1 are the two most promising and established stem-like markers and have been frequently used [ 3 , 5 , 7 , 10 , 15 ]. Studies have reported that LGR5 and ALDH1 expression can reflect the changes in stem-like cells during the process of colorectal tumorigenesis.…”

“…For PCNA and vimentin IHC, sections were incubated overnight at 4°C with primary antibodies: anti-PCNA polyclonal antibody (Abcam, Cambridge, UK) and anti-Vimentin monoclonal antibody (DAKO, Carpinteria, CA, USA), respectively. After primary antibody staining, the slides were washed with PBS-T for 10 minutes, and detection was performed using the Vectastain Elite ABC Kit (Vector Lab., Burlingame, CA, USA) according to the manufacturer's instructions and our published method [ 14 , 15 ]. Next, 3-Amino-9-ethylcarbazole (AEC; Vector Laboratories, Burlingame, CA, USA) was used as the chromogen, and slides were counterstained with Mayer's hematoxylin.…”

Nuclear DICKKOPF-1 as a biomarker of chemoresistance and poor clinical outcome in colorectal cancer

“…Thus, colon cancer stem cells secrete high levels of ALDH1A1 that cause extracellular detoxification of maphosphamide [23] and ALDH1A1 also confers resistance of COLO 205 cells to cyclophosphamide [42]. Consistently, ALDH1A1 expression in colorectal adenoma is associated with a higher risk of metachronous adenoma independent of adenoma size or histopathology [43]. CRC patients with circulating tumor cells expressing ALDH1, survivin and MRP5 have shorter PFS [44], and ALDH1A1 rs1342024 polymorphism associates with shorter time to tumor recurrence [26].…”

Letter from the Editor

“…Building on this and more recent work in the molecular study of premalignancy (4,5), CaPR senior editor Ignacio Wistuba is heading a new minireview series focused on the early pathogenesis of selected human tumors.…”