ALDH1 expression indicates chemotherapy resistance and poor outcome in node-negative rectal cancer.

The cancer stem cell marker aldehyde dehydrogenase 1 (ALDH1) associates with treatment resistance and adverse outcome in several human cancers. We studied ALDH1 expression in rectal cancer, with special emphasis on its association with treatment response and disease outcome. Immunohistochemical staining for ALDH1 was conducted for 64 biopsies and 209 operative samples from rectal cancer patients treated with short- (n = 89) or long-course (n = 46) (chemo)radiotherapy plus surgery, or with surgery only (n = 74). The staining results were compared to clinicopathological variables, tumor regression grade (TRG) and disease outcome. Nuclear ß-catenin expression pattern was analyzed from 197 operative samples. Positive ALDH1 expression was present in 149 operative samples (71%), correlating with deficient nuclear ß-catenin regulation (P = .018). In a pairwise comparison of respective biopsy and operative samples, ALDH1 expression remained stable or increased after preoperative (chemo)radiotherapy in most of the cases, while it decreased in few cases only (P = .02 for positive/negative category; P <.001 for intensity). ALDH1 expression did not, however, relate to tumor regression grade. In node-negative rectal cancer, ALDH1 expression was an independent predictor of short disease-free and disease-specific survival (P = .044; P = .049), specifically among patients treated with adjuvant chemotherapy. We conclude that ALDH1 associates with deregulated ß-catenin signaling, supporting the role of ALDH1 in rectal cancer stemness. ALDH1 expression relates to poor outcome in early stage rectal cancer, a group where new prognostic tools are particularly needed, and may indicate chemo- and radioresistance.

Isoform-specific regulation of the actin-organizing protein palladin during TGF-beta1-induced myofibroblast differentiation.

Contractile myofibroblasts are responsible for remodeling of extracellular matrix during wound healing; however, their continued activity results in various fibrocontractive diseases. Conversion of fibroblasts into myofibroblasts is induced by transforming growth factor-beta1 (TGF-beta1) and is hallmarked by the neo-expression of alpha-smooth muscle actin (alpha-SMA), a commonly used myofibroblast marker. Moreover, myofibroblast differentiation and acquisition of the contractile phenotype involves functionally important alterations in the expression of actin-organizing proteins. We investigated whether myofibroblast differentiation is accompanied by changes in the expression of palladin, a cytoskeletal protein that controls stress fiber integrity. Palladin is expressed as several isoforms, including major 3Ig (90 kDa) and 4Ig (140 kDa) forms that differ in their N-terminal sequence. Expression of the 4Ig isoform is strongly induced in fibroblast stress fibers upon TGF-beta1 treatment preceding alpha-SMA upregulation. TGF-beta1 induced upregulation of palladin is mediated both by Smad and mitogen-activated protein kinase pathways. Furthermore, palladin 4Ig-isoform is co-expressed with alpha-SMA in vivo in experimental rat wounds and in human myofibroblast-containing lesions. Taken together these results identify palladin 4Ig as a novel marker of myofibroblast conversion in vitro and in vivo. They also provide for the first time information about the signaling cascades involved in the regulation of palladin expression.