p21 and CD166 as predictive markers of poor response and outcome after fluorouracil-based chemoradiotherapy for the patients with rectal cancer

Abstract

BackgroundPre-operative chemoradiotherapy (CRT) is the standard treatment in clinical stage T3/4 or node positive rectal cancer. However, there are no established biomarkers that can predict the pathological response and clinical outcome to CRT.MethodsImmunohistochemical staining was performed in tissue arrays constructed from core tissue specimens taken before treatment and from operative specimens from 112 patients who received 5-FU based pre-operative CRT and surgery. Expression of Ki67, TS, BAX, EpCAM, p53, p21, EGFR, CD44, CD133, CD166, HIF1α and ALDH1 were assessed and correlated with tumor regression grades and disease free survival.ResultsOf the 112 patients (M/F 74/38, median age: 62), 20 (17.9%) patients achieved pathologic complete remission (pCR). In analyzing the associations between marker expressions and tumor regression grades, high p21 expression at the pretreatment biopsy was significantly associated with non-pCR (p = 0.022) and poor disease free survival (median DFS - low vs high p21: 75.8 vs 58.1 months, p = 0.002). In the multivariate analysis, high p21 expression level at the pre-treatment biopsy was significantly associated with poor DFS (p = 0.001, HR 6.14; 95% CI 2.03, 18.55). High CD166 expression level at the pretreatment biopsy was also associated with poor DFS (p = 0.003; HR 5.61; 95% CI 1.81, 17.35).ConclusionThese show high p21 and CD166 expression at the pretreatment biopsy were associated with tumor regression and poor prognosis in patients treated with 5-FU based CRT. Larger, prospective and functional studies are warranted to determine the role of p21 and CD166 as predictive biomarker of response to CRT.

EZH2 promotes colorectal cancer stem-like cell expansion by activating p21cip1-Wnt/β-catenin signaling

“…The critical mechanism by which p21 cip1 suppresses CS-like properties is controversial [36–39]. Here, we demonstrated a critical mechanism for the inhibition of Wnt/β-catenin pathway activity by p21 cip1 in CRC.…”

“…However, the role of p21 cip1 in reducing the CS-like cell population is controversial. Studies have suggested that p21 cip1 expression promoted tumor regression and poor prognosis in 112 cancer patients [36, 37], but other studies reported that p21 cip1 expression reduces stem cell properties [38, 39]. Notably, increased p21 signaling in CRC inactivates the Wnt/β-catenin pathway [40].…”

MiR‐17‐5p promotes cancer cell proliferation and tumorigenesis in nasopharyngeal carcinoma by targeting p21

“…MiR-17 directly inhibits the p21 expression in myeloid leukemia [25] and promotes the tumor growth by suppressing p21 in synovial sarcomas [26]. In addition, some previous studies showed that the deletion of p21 led to poor survival prognosis in some cancers [27][28][29][30]. However, the role of the loss of p21 has not been conclusively determined in the clinical outcome of NPC.…”

Complete Pathological Response After Neoadjuvant Long-Course Chemoradiotherapy for Rectal Cancer and Its Relationship to the Degree of T3 Mesorectal Invasion

“…8 Genetic factors may influence the response to chemoradiotherapy and the pCR rate, although there is some debate as to the benefit of some biomarkers. [14][15][16][17] the prognostic differences between t3 early invasion (≤5 mm) compared with more advanced invasion (>5 mm) have been demonstrated. 18 local recurrence rates and 5-year survival rates were improved in t3 patients with early invasion.…”