Aldehyde Dehydrogenase–Expressing Colon Stem Cells Contribute to Tumorigenesis in the Transition from Colitis to Cancer

Abstract

Patients with chronic ulcerative colitis are at increased risk of developing colorectal cancer. Although current hypotheses suggest that sporadic colorectal cancer is due to inability to control cancer stem cells, the cancer stem cell hypothesis has not yet been validated in colitis-associated cancer. Furthermore, the identification of the colitis to cancer transition is challenging. We recently showed that epithelial cells with the increased expression of aldehyde dehydrogenase in sporadic colon cancer correlate closely with tumor-initiating ability. We sought to determine whether ALDH can be used as a marker to isolate tumor-initiating populations from patients with chronic ulcerative colitis. We used fluorescence-activated cell sorting to identify precursor colon cancer stem cells from colitis patients and report both their transition to cancerous stem cells in xenografting studies as well as their ability to generate spheres in vitro. Similar to sporadic colon cancer, these colitis-derived tumors were capable of propagation as sphere cultures. However, unlike the origins of sporadic colon cancer, the primary colitic tissues did not express any histologic evidence of dysplasia. To elucidate a potential mechanism for our findings, we compared the stroma of these different environments and determined that at least one paracrine factor is up-regulated in the inflammatory and malignant stroma compared with resting, normal stroma. These data link colitis and cancer identifying potential tumor-initiating cells from colitic patients, suggesting that sphere and/or xenograft formation will be useful to survey colitic patients at risk of developing cancer. [Cancer Res 2009;69(20):8208-15]

RARα2 expression confers myeloma stem cell features

“…ALDH is a marker of CSCs and a predictor of drug resistance in multiple cancers. 32,33 We examined ALDH activity in RARa2 overexpressing ARP1 and OCI-MY5 cells using the fluorescent ALDH substrate Aldefluor and western-blot analysis. ALDH expression and activity significantly increased in RARa2 overexpressing ARP1 and OCI-MY5 compared with the control cells (Figure 2A-B).…”

Drug-eluting microarrays to identify effective chemotherapeutic combinations targeting patient-derived cancer stem cells

“…Tissues from patients with colon cancer were retrieved under pathological supervision with Institutional Review Board approval from the University of Michigan and the University of Florida as described previously (42).…”

“…Colon cancer stem cells were generated by isolating and enriching for highlevel aldehyde dehydrogenase (ALDH high ) spheres from colon cancer tumor cells obtained from patients with sporadic colorectal cancer (26,27,29,42). Isolated cells were cultured in serum-free media as described previously (26).…”

“…In brief, CCSCs were isolated and enriched for high-level aldehyde dehydrogenase (ALDH high ) activity, a known stem cell enrichment marker, from patients with sporadic colorectal cancer. The ALDH high cells have the definitive CSC property of self-renewal, as demonstrated by the gold standard assay of limiting dilution tumor xenograft analysis (26,27,29,(40)(41)(42)(43). In addition, tumor heterogeneity is maintained, as defined by the ability to recapitulate all cellular aspects of the primary tumor (27,29).…”

Cancer Stem Cells: Formidable Allies of Cancer

“…Subsequent studies have suggested that increased ALDH activity might be a universal marker since it identifies CSCs in liver [42], colon [43], lung [44], melanoma [45], head and neck [46], prostate [47], bladder [48], thyroid [49], glioblastoma [50] and osteosarcoma [51]. The aldefluor assay is used to measure ALDH activity and also allow FACS sorting of ALDH +/high cells.…”