Predictors of tumor response after preoperative chemoradiotherapy for rectal adenocarcinomas

Guedj, Nathalie; Brétagnol, F.; Rautou, Pierre‐Emmanuel; Deschamps, Lydia; Cazals–Hatem, Dominique; Bédossa, Pierre; Couvelard, Anne

doi:10.1016/j.humpath.2011.01.015

Cited by 28 publications

(15 citation statements)

References 33 publications

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“…Previous study has also noted that Hypoxia-inducible factor 1-mediated regulation of PLAUR expression plays a role in the invasiveness of colorectal cancer (53). Tumor hypoxia has been implicated in the mechanisms of resistance to chemoradiotherapy inrectal adenocarcinomas (54), the process of which is mediated by the essential regulator HIF1A, whose overexpression is associated with poor prognosis in colorectal cancers (55). It has been reported that transcriptional up-regulation of FOXM1 in response to hypoxia is mediated by HIF-1A provide a new insight into how tumor cells overcome hypoxic stress and survive (56).…”

Section: Discussionmentioning

confidence: 99%

The Critical Role of Dysregulated FOXM1–PLAUR Signaling in Human Colon Cancer Progression and Metastasis

Wei

Peng

et al. 2013

Clinical Cancer Research

102

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Purpose The mammalian Forkhead Box (Fox) transcription factor FOXM1 is implicated in tumorigenesis including mouse intestinal cancer. However, the clinical significance of FOXM1 signaling in human colorectal cancer (CRC) pathogenesis remains unknown. Experimental Design We investigated FOXM1 expression in 203 cases of primary colon cancer and matched normal colon tissue specimens and explored the underlying mechanisms of altered FOXM1 expression and the impact of this altered expression on colon cancer growth and metastasis using in vitro and animal models of colon cancer. Results We found weak expression of FOXM1 protein in the colon mucosa, whereas we observed strong FOXM1 expression in tumor-cell nuclei of colon cancer and lymph node metastases. A Cox proportional hazards model revealed that FOXM1 expression was an independent prognostic factor in multivariate analysis. Experimentally, overexpression of FOXM1 by gene transfer significantly promoted the growth and metastasis of colon cancer cells in orthotopic mouse models, whereas knockdown of FOXM1 expression by small interfering RNA did the opposite. Promotion of colon tumorigenesis by FOXM1 directly and significantly correlated with activation of urokinase plasminogen activator receptor (PLAUR) expression and elevation of invasion and metastasis. Conclusions Given the importance of FOXM1 in regulation of the expression of genes key to cancer biology, dysregulated expression and activation of FOXM1 may play important roles in colon cancer progression and metastasis.

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Section: Discussionmentioning

confidence: 99%

The Critical Role of Dysregulated FOXM1–PLAUR Signaling in Human Colon Cancer Progression and Metastasis

Wei

Peng

et al. 2013

Clinical Cancer Research

102

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“…Colorectal tumors are often large, and analysis of hypoxia biomarkers in patient samples has revealed that most tumors exhibit a molecular phenotype consistent with varying hypoxia [11]. Moreover, in a recent report, expression of the hypoxia-associated protein carbonic anhydrase IX was negatively associated with CRT response in patients with rectal cancer [14]. Hence, a likely explanation for variable CRT response in rectal cancer is variable tumor oxygenation, and in this perspective, the ability to overcome hypoxia-related radioresistance would be an advantageous property of a radiosensitizing drug.…”

Section: Discussionmentioning

confidence: 99%

Radiosensitization by the histone deacetylase inhibitor vorinostat under hypoxia and with capecitabine in experimental colorectal carcinoma

et al. 2012

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BackgroundThe histone deacetylase inhibitor vorinostat is a candidate radiosensitizer in locally advanced rectal cancer (LARC). Radiosensitivity is critically influenced by hypoxia; hence, it is important to evaluate the efficacy of potential radiosensitizers under variable tissue oxygenation. Since fluoropyrimidine-based chemoradiotherapy (CRT) is the only clinically validated regimen in LARC, efficacy in combination with this established regimen should be assessed in preclinical models before a candidate drug enters clinical trials.MethodsRadiosensitization by vorinostat under hypoxia was studied in four colorectal carcinoma cell lines and in one colorectal carcinoma xenograft model by analysis of clonogenic survival and tumor growth delay, respectively. Radiosensitizing effects of vorinostat in combination with capecitabine were assessed by evaluation of tumor growth delay in two colorectal carcinoma xenografts models.ResultsUnder hypoxia, radiosensitization by vorinostat was demonstrated in vitro in terms of decreased clonogenicity and in vivo as inhibition of tumor growth. Adding vorinostat to capecitabine-based CRT increased radiosensitivity of xenografts in terms of inhibited tumor growth.ConclusionsVorinostat sensitized colorectal carcinoma cells to radiation under hypoxia in vitro and in vivo and improved therapeutic efficacy in combination with capecitabine-based CRT in vivo. The results encourage implementation of vorinostat into CRT in LARC trials.

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“…In fact, it is also reported that hypoxia was an essential “niche” for CD133 to maintain CSC ability in glioblastoma [45]. On the other hand, hypoxia is known to be significantly correlated with resistance to preoperative CRT in rectal cancer [46, 47]. Considering these facts, it is suggested that a hypoxic niche may contribute to enhanced CD133 expression after CRT in rectal cancer tissue and may also affect the prognosis of patients.…”

Section: Discussionmentioning

confidence: 99%

Immunohistochemical detection of CD133 is associated with tumor regression grade after chemoradiotherapy in rectal cancer

et al. 2012

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CD133 has been identified as a putative cancer stem cell (CSC) marker in various cancers including colorectal cancer. The relation between CD133 expression and biological characteristics of colorectal cancer remains to be clarified. Protein expression of CD133 was immunohistochemically evaluated in surgical specimens of 225 patients with colorectal cancer who were treated by surgery, as well as those of 78 patients with rectal cancer who received preoperative chemoradiotherapy (CRT) followed by curative resection. The correlation between CD133 expression and clinicopathological features, tumor recurrence and overall survival was analyzed in both populations. Among 225 colorectal cancers without CRT, 93 (41.3%) were positive for CD133 expression, which was enhanced in cases with advanced T stage and venous invasion. Moreover, CD133 was positive in 47 (60.3%) of 78 cases with CRT, which was significantly higher than the CD133-positive rate in non-CRT specimens (P = 0.05). Expression of CD133 was independently correlated with the histological tumor regression grade (P < 0.01). These results suggest that CD133 is not a distinctive colorectal CSC marker; expression of CD133 is suggested to be one of the key factors associated with resistance to CRT in colorectal cancer.

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Predictors of tumor response after preoperative chemoradiotherapy for rectal adenocarcinomas

Cited by 28 publications

References 33 publications

The Critical Role of Dysregulated FOXM1–PLAUR Signaling in Human Colon Cancer Progression and Metastasis

The Critical Role of Dysregulated FOXM1–PLAUR Signaling in Human Colon Cancer Progression and Metastasis

Radiosensitization by the histone deacetylase inhibitor vorinostat under hypoxia and with capecitabine in experimental colorectal carcinoma

Immunohistochemical detection of CD133 is associated with tumor regression grade after chemoradiotherapy in rectal cancer

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