Colorectal cancer tumour markers and biomarkers:Recenttherapeutic advances

Colorectal cancer(CRC) is the second most commonly diagnosed cancer among females and third among males worldwide. It also contributes significantly to cancer-related deaths, despite the continuous progress in diagnostic and therapeutic methods. Biomarkers currently play an important role in the detection and treatment of patients with colorectal cancer. Risk stratification for screening might be augmented by finding new biomarkers which alone or as a complement of existing tests might recognize either the predisposition or early stage of the disease. Biomarkers have also the potential to change diagnostic and treatment algorithms by selecting the proper chemotherapeutic drugs across a broad spectrum of patients. There are attempts to personalise chemotherapy based on presence or absence of specific biomarkers. In this review, we update review published last year and describe our understanding of tumour markers and biomarkers role in CRC screening, diagnosis, treatment and follow-up. Goal of future research is to identify those biomarkers that could allow a non-invasive and cost-effective diagnosis, as well as to recognise the best prognostic panel and define the predictive biomarkers for available treatments.

Non-polypoid colorectal neoplasms:Classification,therapy and follow-up

In the last years,an increasing interest has been raised on non-polypoid colorectal tumors(NPT) and in particular on large flat neoplastic lesions beyond 10 mm tending to grow laterally,called laterally spreading tumors(LST).LSTs and large sessile polyps have a greater frequency of high-grade dysplasia and local invasiveness as compared to pedunculated lesions of the same size and usually represent a technical challenge for the endoscopist in terms of either diagnosis and resection.According to the Paris classification,NPTs are distinguished in slightly elevated(0-Ⅱa,less than 2.5 mm),flat(0-Ⅱb) or slightly depressed(0-Ⅱc).NPTs are usually flat or slightly elevated and tend to spread laterally while in case of depressed lesions,cell proliferation growth progresses in depth in the colonic wall,thus leading to an increased risk of submucosal invasion(SMI) even for smaller neoplasms.NPTs may be frequently missed by inexperienced endoscopists,thus a careful training and precise assessment of all suspected mucosal areas should be performed.Chromoendoscopy or,if possible,narrow-band imaging technique should be considered for the estimation of SMI risk of NPTs,and the characterization of pit pattern and vascular pattern may be useful to predict the risk of SMI and,therefore,to guide the therapeutic decision.Lesions suitable to endoscopic resection are those confined to the mucosa(or superficial layer of submucosa in selected cases) whereas deeper invasion makes endoscopic therapy infeasible.Endoscopic mucosal resection(EMR,piecemeal for LSTs > 20 mm,en bloc for smaller neoplasms) remains the first-line therapy for NPTs,whereas endoscopic submucosal dissection in high-volume centers or surgery should be considered for large LSTs for which en bloc resection is mandatory and cannot be achieved by means of EMR.After piecemeal EMR,follow-up colonoscopy should be performed at 3 mo to assess resection completeness.In case of en bloc resection,surveillance colonoscopy should be scheduled at 3 years for adenomatous lesions ≥ 1 cm,or in presence of villous features or high-grade dysplasia patients(regardless of the size),while less intensive surveillance(colonoscopy at 5-10 years) is needed in case of single(or two) NPT < 1 cm presenting tubular features or low-grade dysplasia at histology.

Hypoalbuminemia in colorectal cancer prognosis:Nutritional marker or inflammatory surrogate?

Albumin is the single most abundant protein in the human serum. Its roles in physiology and pathology are diverse. Serum albumin levels have been classically thought to reflect the nutritional status of patients. This concept has been challenged in the last two decades as multiple factors, such as inflammation, appeared to affect albumin levels independent of nutrition. In general, cancer patients have a high prevalence of hypoalbuminemia. As such, the role of hypoalbuminemia in patients with colorectal cancer has received significant interest. We reviewed the English literature on the prognostic value of pretreatment albumin levels in colorectal cancer. We also consolidated the evidence that led to the current understanding of hypoalbuminemia as an inflammatory marker rather than as a nutritional one among patients with colorectal cancer.

CREB-binding protein, p300, butyrate, and Wnt signaling in colorectal cancer

This paper reviews the distinctive roles played by the transcriptional coactivators CREB-binding protein(CBP) and p300 in Wnt/β-catenin signaling and cell physiology in colorectal cancer(CRC). Specifically, we focus on the effects of CBP- and p300-mediated Wnt activity on(1) neoplastic progression;(2) the activities of butyrate, a breakdown product of dietary fiber, on cell signaling and colonic cell physiology;(3) the development of resistance to histone deacetylase inhibitors(HDACis), including butyrate and synthetic HDACis, in colonic cells; and(4) the physiology and number of cancer stem cells. Mutations of the Wnt/β-catenin signaling pathway initiate the majority of CRC cases, and we have shown that hyperactivation of this pathway by butyrate and other HDACis promotes CRC cell apoptosis. This activity by butyrate may in part explain the preventive action of fiber against CRC. However, individuals with a high-fiber diet may still develop neoplasia; therefore, resistance to the chemopreventive action of butyrate likely contributes to CRC. CBP or p300 may modify the ability of butyrate to influence colonic cell physiology since the two transcriptional coactivators affect Wnt signaling, and likely, its hyperactivation by butyrate. Also, CBP and p300 likely affect colonic tumorigenesis, as well as stem cell pluripotency. Improvement of CRC prevention and therapy requires a better understanding of the alterations in Wnt signaling and gene expression that underlie neoplastic progression, stem cell fate, and the development of resistance to butyrate and clinically relevant HDACis. Detailed knowledge of how CBP- and p300 modulate colonic cell physiology may lead to new approaches for anti-CRC prevention and therapeutics, particularly with respect to combinatorial therapy of CBP/p300 inhibitors with HDACis.

Hypoxia-inducible factor-1 modulates upregulation of mutT homolog-1 in colorectal cancer

AIM: To investigate the roles and interactions of mut T homolog(MTH)-1 and hypoxia-inducible factor(HIF)-1α in human colorectal cancer(CRC).METHODS: The expression and distribution of HIF-1α and MTH-1 proteins were detected in human CRC tissues by immunohistochemistry and quantitative realtime polymerase chain reaction(q RT-PCR). SW480 and HT-29 cells were exposed to normoxia or hypoxia. Protein and m RNA levels of HIF-1α and MTH-1 were analyzed by western blotting and q RT-PCR, respectively. In order to determine the effect of HIF-1α on the expression of MTH-1 and the amount of 8-oxodeoxyguanosine triphosphate(d GTP) in SW480 and HT-29 cells, HIF-1α was silenced with small interfering RNA(si RNA). Growth studies were conducted on cells with HIF-1α inhibition using a xenograft tumor model. Finally, MTH-1 protein was detected by western blotting in vivo.RESULTS: High MTH-1 m RNA expression was detected in 64.2% of cases(54/84), and this was significantly correlated with tumor stage(P = 0.023) and size(P = 0.043). HIF-1α protein expression was correlated significantly with MTH-1 expression(R = 0.640; P < 0.01) in human CRC tissues. Hypoxic stress induced m RNA and protein expression of MTH-1 in SW480 and HT-29 cells. Inhibition of HIF-1α by si RNA decreased the expression of MTH-1 and led to the accumulation of 8-oxo-d GTP in SW480 and HT-29 cells. In the in vivo xenograft tumor model, expression of MTH-1 was decreased in the HIF-1α si RNA group, and the tumor volume was much smaller than that in the mock si RNA group.CONCLUSION: MTH-1 expression in CRC cells was upregulated via HIF-1α in response to hypoxic stress, emphasizing the crucial role of HIF-1α-induced MTH-1 in tumor growth.

Role of a liver-first approach for synchronous colorectalliver metastases

AIM: To evaluate the feasibility and survival outcomes of a liver-first approach.METHODS: Between January 2009 and April 2013, 18 synchronous colorectal liver metastases(s CRLMs) patients with a planned liver-first approach in the Hepatopancreatobiliary Surgery Department Ⅰ of the Beijing Cancer Hospital were enrolled in this study. Clinical data, surgical outcomes, morbidity and mortality rates were collected. The feasibility and long-term outcomes of the approach were retrospectively analyzed.RESULTS: Sixteen patients(88.9%) completed the treatment protocol for primary and liver tumors. The main reason for treatment failure was liver disease recurrence. The 1 and 3 year overall survival rates were 94.4% and 44.8%, respectively. The median survival time was 30 mo. The postoperative morbidity and mortality were 22.2% and 0%, respectively, following a hepatic resection, and were 18.8% and 0%, respectively, after a colorectal surgery.CONCLUSION: The liver-first approach appeared to be feasible and safe. It can be performed with a comparable mortality and morbidity to the traditional treatment paradigm. This approach might offer a curative opportunity for s CRLM patients with a high liver disease burden.

Long-term outcomes after stenting as a"bridge to surgery"for the management of acute obstruction secondary tocolorectal cancer

Obstructive symptoms are present in 8% of cases at the time of initial diagnosis in cases of colorectal cancer. Emergency surgery has been classically considered the treatment of choice in these patients. However, in the majority of studies, emergency colorectal surgery is burdened with higher morbidity and mortality rates than elective surgery, and many patients require temporal colostomy which deteriorates their quality of life and becomes permanent in 10%-40% of cases. The aim of stenting by-pass to surgery is to transform emergency surgery into elective surgery in order to improve surgical results, obtain an accurate tumoral staging and detection of synchronous lesions, stabilization of comorbidities and performance of laparoscopic surgery. Immediate results were more favourable in patients who were stented concerning primary anastomosis, permanent stoma, wound infection and overall morbidity, having the higher surgical risk patients the greater benefit. However, some findings laid out the possible implication of stenting in long-term results of oncologic treatment. Perforation after stenting is related to tumoral recurrence. In studies with perforation rates above 8%, higher recurrences rates in young patients and lower disease free survival have been shown. On the other hand, after stenting the number of removed lymph nodes in the surgical specimen is larger, patients can receive adjuvant chemotherapy earlier and in a greater percentage and the number of patients who can be surgically treated with laparoscopic surgery is larger. Finally, there are no consistent studies able to demonstrate that one strategy is superior to the other in terms of oncologic benefits. At present, it would seem wise to assume a higher initial complication rate in young patients without relevant comorbidities and to accept the risk of local recurrence in old patients(> 70 years) or with high surgical risk(ASA Ⅲ/Ⅳ).

Anti-angiogenic agents in metastatic colorectal cancer

Colorectal cancer(CRC) is a major public health concern being the third leading cause of cancer mortality in the United States. The availability of better therapeutic options has led to a decline in cancer mortality in these patients. Surgical resection should be considered in all stages of the disease. The use of conversion therapy has made surgery a potentially curative option even in patients with initially unresectable metastatic disease. In this review we discuss the role of various antiangiogenic agents in patients with metastatic CRC(m CRC). We describe the mechanism of action of these agents, and the rationale for their use in combination with chemotherapy. We also review important clinical studies that have evaluated the safety and efficacy of these agents in m CRC patients. Despite the discovery of several promising anti-angiogenic agents, m CRC remains an incurable disease with a median overall survival of just over 2 years in patients exposed to all available treatment regimens. Further insights into tumor biology and tumor microenvironment may help improve outcomes in these patients.

MiR-139-5p inhibits migration and invasion of colorectal cancer by downregulating AMFR and NOTCH1

MicroRNAs （miRNAs） that exert function by posttran- scriptional suppression have recently brought insight in our understanding of the role of non.protein-coding RNAs in carcinogenesis and metastasis. In this study, we described the function and molecular mechanism of miR-139-5p in colorectal cancer （CRC） and its potential clinical application in CRC. We found that miR-139-5p was significantly downregulated in 73.8% CRC samples compared with adjacent noncancerous tissues （NCTs）, and decreased miR-139-5p was associated with poor prognosis. Functional analyses demonstrated that ectopic expression of miR-139-5p suppressed CRC cell migration and invasion in vitro and metastasis in vivo. Mechanistic investigations revealed that miR-139-5p suppress CRC cell invasion and metastasis by targeting AMFR and NOTCH1. Knockdown of the two genes phe- nocopied the inhibitory effect of miR-139-5p on CRC metastasis. Furthermore, the protein levels of the two genes were upregulated in CRC samples compared with NCTs, and inversely correlated with the miR-139-5p expression. Increased NOTCH1 protein expression was correlated with poor prognosis of CRC patients. Together, our data indicate that miR-139-5p is a potentialtumor suppressor and prognostic factor for CRC, and targeting miR-139-5p may repress the metastasis of CRC and improve survival.