The mushroom Ganoderma lucidum (G. lucidum) has been consumed in China as a medicine for promoting health and longevity for thousands of years. Due to its paramount and multiple pharmaceutical effects, G. lucidum has received considerable attention from researchers and its chemical constituents as well as their respective functions were gradually unveiled by using modern research methods. Herein, we reported the isolation of a protein (Ganoderma lucidum ribonuclease, GLR) with anti-colorectal cancer activities from G. lucidum. This protein is a 17.4-kDa RNA degrading enzyme (ribonuclease) and was purified by using liquid chromatography procedures. GLR manifested potent anti-proliferative and anti-colony formation activities on HT29 and HCT116 colorectal cancer cells by inducing cell cycle arrest in G1 phase through the regulation of cyclin D1 and P53 expression. GLR was demonstrated to induce cell apoptosis in HCT116 cells by activating unfolded protein response and caspase-9 regulated pathways. Besides, the ability to undergo autophagy which is a stress adaption mechanism to cope with metabolic crisis was significantly suppressed by GLR treatment in HCT116 cells. The activation of apoptosis in GLR-treated HT29 cells was, however, independent of caspase-9 and the suppression of autophagy was also relatively minor. Thus the apoptosis of HT29 cells triggered by GLR was much milder than that in HCT116 cells. Our findings show that the RNase from G. lucidum may be one of the bioactive components that contribute to the anti-colorectal cancer activity of G. lucidum.

PURPOSE:Regular physical activity is associated with reduced risk of recurrence and mortality in patients with nonmetastatic colorectal cancer. Its influence on patients with advanced/metastatic colorectal cancer (mCRC) has been largely unexplored.

PATIENTS AND METHODS:We conducted a prospective cohort study nested in Cancer and Leukemia Group B (Alliance)/SWOG 80405 (ClinicalTrials.gov identifier: NCT00265850), a National Cancer Institute-sponsored phase III trial of systemic therapy for mCRC. Within 1 month after therapy initiation, patients were invited to complete a validated questionnaire that reported average physical activity over the previous 2 months. On the basis of responses, we calculated metabolic equivalent task (MET) hours per week to quantify physical activity. The primary end point of the clinical trial and this companion study was overall survival (OS). Secondary end points included progression-free survival (PFS) and first grade 3 or greater treatment-related adverse events. To minimize confounding by poor and declining health, we excluded patients who experienced progression or died within 60 days of activity assessment and used Cox proportional hazards regression analysis to adjust for known prognostic factors, comorbidities, and weight loss.

RESULTS:The final cohort included 1,218 patients. Compared with patients engaged in less than 3 MET hours per week of physical activity, patients engaged in 18 or more MET hours per week experienced an adjusted hazard ratio for OS of 0.85 (95% CI, 0.71 to 1.02;= .06) and for PFS of 0.83 (95% CI, 0.70 to 0.99;= .01). Compared with patients engaging in less than 9 MET hours per week, patients engaging in 9 or more MET hours per week experienced an adjusted hazard ratio for grade 3 or greater treatment-related adverse events of 0.73 (95% CI, 0.62 to 0.86;<.001).

CONCLUSION:Among patients with mCRC in Cancer and Leukemia Group B (Alliance)/SWOG 80405, association of physical activity with OS was not statistically significant. Greater physical activity was associated with longer PFS and lower adjusted risk for first grade 3 or greater treatment-related adverse events.

Targeting autophagy may serve as a promising strategy for cancer therapy. Ganoderma lucidum polysaccharide (GLP) has been shown to exert promising anti-cancer effects. However, the underlying mechanisms remain elusive. Whether GLP regulates autophagy in cancer has never been reported. In this study, GLP induced the initiation of autophagy in colorectal cancer (CRC) HT-29 and HCT116 cells, as evidenced by enhanced level of LC3-II protein, GFP-LC3 puncta, and increased formation of double membrane vacuoles. However, GLP treatment caused marked increase of p62 expression. Addition of late stage autophagy inhibitor, chloroquine (CQ), further enhanced LC3-II and p62 level, as well as increased autophagosome accumulation, suggesting a blockage of autophagic flux by GLP in CRC cells. We then found GLP blocked autophagosome and lysosome fusion as determined by mRFP-GFP-LC3 colocalization analysis. Mechanistic study revealed that GLP-induced disruption of autophagosome-lysosome fusion is due to reduced lysosome acidification and lysosomal cathepsin activities. Cell viability and flow cytometry assays revealed that GLP-induced autophagosome accumulation is responsible for GLP-induced apoptosis in CRC cells. In line with this, inhibition of autophagy initiation by 3-methyladenine (3-MA), an early stage autophagy inhibitor, attenuated GLP-induced apoptosis. In contrast, suppression of autophagy at late stage by CQ enhanced the anti-cancer effect of GLP. Furthermore, we demonstrated that GLP-induced autophagosome accumulation and apoptosis is mediated via MAPK/ERK activation. Finally, GLP inhibited tumor growth and also inhibited autophagic flux in vivo. These results unveil new molecular mechanism underlying anti-cancer effects of GLP, suggesting that GLP is a potent autophagy inhibitor and might be useful in anticancer therapy.

Vitamin C, available in its reduced form (ascorbic acid; AA) and in its oxidized form (dehydroascorbic acid; DHA), may act in physiological conditions as an antioxidant or pro-oxidant. The aim of this study is to evaluate the cytotoxic effects of pharmacological doses of AA in a human colorectal adenocarcinoma cell line (WiDr) in vitro, through spectrophotometry, clonogenic assays and flow cytometry, and in vivo with xenotransplanted Balb/c nu/nu mice. The results show that the reduced form of vitamin C induces an anti-proliferative and cytotoxic effect in adenocarcinoma colorectal cells under study. The results obtained in vivo after treatment with AA showed a large reduction in the rate of tumor growth. Such understanding can guide decisions about which colorectal cancer patients might potentially benefit from vitamin C pharmacologic therapy.

UNLABELLED:Background/Aim: This paper reviews ecological studies of the ultraviolet-B (UVB)-vitamin D-cancer hypothesis based on geographical variation of cancer incidence and/or mortality rates.

MATERIALS AND METHODS:The review is based largely on three ecological studies of cancer rates from the United States; one each from Australia, China, France, Japan, and Spain; and eight multicountry, multifactorial studies of cancer incidence rates from more than 100 countries.

RESULTS:This review consistently found strong inverse correlations with solar UVB for 15 types of cancer: bladder, breast, cervical, colon, endometrial, esophageal, gastric, lung, ovarian, pancreatic, rectal, renal, and vulvar cancer; and Hodgkin's and non-Hodgkin's lymphoma. Weaker evidence exists for nine other types of cancer: brain, gallbladder, laryngeal, oral/pharyngeal, prostate, and thyroid cancer; leukemia; melanoma; and multiple myeloma.

CONCLUSION:The evidence for the UVB-vitamin D-cancer hypothesis is very strong in general and for many types of cancer in particular.

BACKGROUND:Cancer-related fatigue (CRF) is one of the most troubling symptoms of cancer patients during chemotherapy, and no gold standard for the treatment of CRF has been established.

OBJECTIVE:This study aimed to examine the effects of the Baduanjin qigong on patients with colorectal cancer and CRF, and to explore its intervention effects.

METHODS:This was an open-label, randomized controlled clinical trial. Ninety patients with chemotherapy-treated colorectal cancer and CRF were randomized to a Baduanjin exercise group or a routine care group. The primary outcome was the Brief Fatigue Inventory (BFI) score at 24 weeks. The secondary outcomes were the Karnofsky Performance Status (KPS) and Pittsburgh Sleep Quality Index (PSQI) scores at 24 weeks.

RESULTS:There were no significant differences between the two groups in CRF level at baseline and 12 weeks. At 24 weeks, the proportion of patients with moderate-to-severe CRF was significantly smaller in the exercise group than in the control group (23.2 vs. 59.1%, p<0.01). The KPS and PSQI scores were similar in the two groups at baseline and 12 weeks, but they were significantly higher and lower, respectively, at 24 weeks in the exercise group compared with the control group (KPS score: 89.3± 8.3 vs. 75.2 ± 11.5, p<0.01; PSQI score: 4.1± 1.1 vs. 6.9 ± 2.0, p<0.01). Significant time-group interactions were observed for all three scores (all p<0.01).

CONCLUSIONS:Baduanjin qigong exercise can relieve CRF in patients with colorectal cancer undergoing chemotherapy and can improve their physical activity level and their quality of sleep.

BACKGROUND:Patients with colorectal cancer are usually treated with chemotherapy, which reduces the number of blood cells, especially white blood cells, and consequently increases the risk of infections. Some research studies have reported that aromatherapy massage affects the immune system and improves immune function by, for example, increasing the numbers of natural killer cells and peripheral blood lymphocytes. However, there has been no report of any study which provided good evidence as to whether aromatherapy with Thai massage could improve the immune system in patients with colorectal cancer. The objectives of this study were to determine whether the use of aromatherapy with light Thai massage in patients with colorectal cancer, who have received chemotherapy, can result in improvement of the cellular immunity and reduce the severity of the common symptoms of side effects.

MATERIALS AND METHODS:Sixty-six patients with colorectal cancer in Phichit Hospital, Thailand, were enrolled in a single-blind, randomised-controlled trial. The intervention consisted of three massage sessions with ginger and coconut oil over a 1-week period. The control group received standard supportive care only. Assessments were conducted at pre-assessment and at the end of one week of massage or standard care. Changes from pre-assessment to the end of treatment were measured in terms of white blood cells, neutrophils, lymphocytes, CD4 and CD8 cells and the CD4/CD8 ratio and also the severity of self-rated symptom scores.

RESULTS:The main finding was that after adjusting for pre-assessment values the mean lymphocyte count at the post-assessment was significantly higher (P=0.04) in the treatment group than in the controls. The size of this difference suggested that aromatherapy with Thai massage could boost lymphocyte numbers by 11%. The secondary outcomes were that at the post assessment the symptom severity scores for fatigue, presenting symptom, pain and stress were significantly lower in the massage group than in the standard care controls.

CONCLUSIONS:Aromatherapy with light Thai massage can be beneficial for the immune systems of cancer patients who are undergoing chemotherapy by increasing the number of lymphocytes and can help to reduce the severity of common symptoms.

This randomized controlled clinical study aimed to determine the effect of 2 foot massage methods on symptom control in people with colorectal cancer who received chemoradiotherapy. Data were collected between June 16, 2015, and February 10, 2016, in the Department of Radiation Oncology of an oncology training and research hospital. The sample comprised 60 participants. Data were collected using an introductory information form, common terminology criteria for adverse events and European Organization for Research and Treatment of Cancer Quality of Life Questionnaires C30 and CR29. Participants were randomly allocated to 3 groups: classical foot massage, reflexology, and standard care control. The classical massage group received foot massage using classical massage techniques, and the reflexology group received foot reflexology focusing on symptom-oriented reflexes twice a week during a 5-week chemoradiotherapy treatment schedule. The control group received neither classical massage nor reflexology. All patients were provided with the same clinic routine care. The classical massage was effective in reducing pain level and distension incidence while foot reflexology was effective in reducing pain and fatigue level, lowering incidence of distension and urinary frequency and improving life quality.

Dietary restriction has been recognized as a healthy and natural therapy for cancer. It is reported that different forms of dietary restriction can promote anti-tumor immunity. However, it is not clear how fasting affects tumor-associated macrophages (TAMs). This study aims to investigate the relationship between fasting and antitumor immunity in terms of tumor-associated macrophages. In vivo, the results showed that alternate day fasting for 2 weeks inhibitted the tumor growth of mice without causing a reduction of body weight. Meanwhile, M2 polarization of tumor-associated macrophages in tumor tissues of alternate day fasting group was also decreased. In vitro, fasting induced the autophagy of CT26 cells, decreased the generation of extracellular adenosine by supressing the expression of CD73 in CT26 cells. Decreasing adenosine inhibitted M2 polarization of RAW264.7 cells through inactivating JAK1/STAT3 signal pathway in fasting condition. Eventually, the proliferation of CT26 cancer cells declined on account of fasting-facilitated antitumor immunity. These results suggested that fasting suppressed M2 polarization of tumor-associated macrophages to inhibit tumor growth through decreasing the level of adenosine in the tumor microenvironment both in vivo and in vitro. This process was associated with increasing autophagy of tumor cells.

Liver resection is the treatment of choice for resectable hepatic metastases; however, most patients have unresectable disease when diagnosed. Hepatic cryotherapy has been advocated to treat unresectable tumours in the liver although its precise role is still being evaluated. This article discusses mechanisms of action, technical considerations, current indications and the early results of cryotherapy in treating metastatic liver disease.

Ascorbate is a co-factor for the hydroxylases that regulate the transcription factor hypoxia-inducible factor (HIF)-1, which provides cancer cells with a metabolic and survival advantage in the hypoxic environment of solid tumors. However, whether ascorbate affects tumor development is a highly debated issue. We aimed to determine whether tumor ascorbate was associated with HIF-1 activation and patient disease-free survival. In this study, we undertook a retrospective observational analysis of tissue-banked tumor and paired normal tissue from 49 colorectal cancer patients, measuring ascorbate levels, HIF-1α and its downstream gene products BNIP3, and vascular endothelial cell growth factor (VEGF). Patient survival was monitored for the first 6 years after surgery. We found that ascorbate levels were lower in tumor tissue compared to normal tissue (p < 0.001) but overall levels varied considerably. HIF-1α, VEGF, and BNIP3 were elevated in tumor samples (p < 0.01). There was an inverse relationship between tumor ascorbate content and HIF-1 pathway activation (p = 0.002) and tumor size (p = 0.018). Higher tumor ascorbate content was associated with significantly improved disease-free survival in the first 6 years after surgery (p = 0.006), with 141-1,094 additional disease-free days. This was independent of tumor grade and stage. Survival advantage was associated with the amount of ascorbate in the tumor, but not with the amount in adjacent normal tissue. Our results demonstrate that higher tumor ascorbate content is associated with decreased HIF-1 activation, most likely due to the co-factor activity of ascorbate for the regulatory HIF hydroxylases. Our findings support the need for future studies to determine whether raising tumor ascorbate is possible with clinical intervention and whether this results in modification of hydroxylase-dependent pathways in the tumor.

Because of irregular dietary habits and lifestyle in Taiwan, the incidence and mortality rate of colorectal cancer have been increasing rapidly these years. This study investigated the inhibitory activity against the proliferation of human colorectal cancer HCT-116 cells by Inonotus obliquus extracts obtained from submerged fermentation. Cell viability was measured by the reduction of MTT and cell membrane integrity was determined by lactic dehydrogenase (LDH) release. The mRNA expression of proapoptosis and antiapoptosis mediators was assayed by real-time PCR, and the levels of p53 and NF-κB p65 were assessed using Western blot analysis. Furthermore, the influences of I. obliquus extracts to HCT-116 cells were evaluated by caspase-3 activity. The results can be summarized as, for the mitochondrial apoptotic pathway, quantitative RT-PCR data showed up-regulation of proapoptotic genes(Bax, bad, and caspase-3) and increased Bax/bcl-2 ratio by I. obliquus extracts. Moreover, treating with 20 mg/mL I. obliquus extracts augmented caspase-3 activity in HCT-116 cells. Induction of cell cycle G0/G1 phase arrest: I. obliquus extracts up-regulated the mRNA expression of proapoptotic genes (p53, p21WAF1/CIP1) and down-regulated antiapoptotic gene (CyclinD1), while extracts of I. obliquus mycelia increased the expressions of p53 protein in HCT-116 cells. I. obliquus extracts decreased the expression of NF-κB p65 protein and COX-2 gene in HCT-116 cells. Taking together, I. obliquus extracts may be used as a potentially novel food material for health care to improve the treatment of colorectal cancer.

PURPOSE:To assess if the associations found between three previously identified dietary patterns with breast, prostate and gastric cancer are also observed for colorectal cancer (CRC).

METHODS:MCC-Spain is a multicase-control study that collected information of 1629 incident cases of CRC and 3509 population-based controls from 11 Spanish provinces. Western, Prudent and Mediterranean data-driven dietary patterns-derived in another Spanish case-control study-were reconstructed in MCC-Spain. Their association with CRC was assessed using mixed multivariable logistic regression models considering a possible interaction with sex. Risk by tumor site (proximal colon, distal colon, and rectum) was evaluated using multinomial regression models.

RESULTS:While no effect of the Prudent pattern on CRC risk was observed, a high adherence to the Western dietary pattern was associated with increased CRC risk for both males [OR(95% CI): 1.45 (1.11;1.91)] and females [OR(95% CI): 1.50 (1.07;2.09)] but seem to be confined to distal colon [OR(95% CI): 2.02 (1.44;2.84)] and rectal [OR(95% CI): 1.46 (1.05;2.01)] tumors. The protective effect of the Mediterranean dietary pattern against CRC was observed for both sexes [males: OR(95% CI): 0.71 (0.55;0.92); females: OR(95% CI): 0.56 (0.40;0.77)] and for all cancer sites: proximal colon [OR(95% CI): 0.70 (0.51;0.97)], distal colon [OR(95% CI): 0.65 (0.48;0.89)], and rectum (OR(95% CI): 0.60 (0.45;0.81)].

CONCLUSION:Our results are consistent with most of the associations previously found between these patterns and breast, prostate and gastric cancer risk and indicate that consuming whole fruits, vegetables, legumes, olive oil, nuts, and fish and avoiding red and processed meat, refined grains, sweets, caloric drinks, juices, convenience food, and sauces might reduce CRC risk.

AIM:To evaluate the association between the Mediterranean diet (MD) pattern and its components, and advanced colorectal polyps (adenoma and serrated adenoma).

METHODS:A case-control study among patients undergoing screening, diagnostic or surveillance colonoscopies during 2010-2015 at the Tel-Aviv Medical Center, Gastroenterology Department. Cases with advanced polyps were defined as: Advanced adenoma [>10 mm, with features of high grade dysplasia (HGD) or villous histology], advanced serrated adenoma (>10 mm or with dysplasia) or multiple (≥ 3) non-advanced adenomas or serrated adenomas. Cases of non-advanced adenomas were defined as adenomas<10 mm, without features of HGD or villous histology. Controls were defined as those without polyps at the current colonoscopy and without a history of colorectal polyps. Data collection included: anthropometrics measured according to a standardized protocol, fasting blood tests performed at the same lab, medical history recorded by a structured interview and dietary intake evaluated by a 116-item food frequency questionnaire. Adherence to the MD components was evaluated according to intake above/below the sample median, for potentially beneficial/detrimental components respectively, as accepted.

RESULTS:We recruited 206 cases with advanced polyps, 192 cases with non-advanced adenoma and 385 controls. The number of adhered MD components was inversely associated with a diagnosis of advanced polyps in a dose-response manner (OR = 0.34, 95%CI: 0.17-0.65; OR = 0.22, 95%CI: 0.11-0.43; and OR = 0.18, 95%CI: 0.07-0.47 for 3-4, 5-7 and 8-10 components, respectively), but not with non-advanced adenomas (OR = 0.54, 95%CI: 0.25-1.13; OR = 0.48, 95%CI: 0.23-0.99; and OR = 0.43, 95%CI: 0.16-1.12 for 3-4, 5-7 and 8-10 components, respectively). Low intake of sugar-sweetened beverages and red meat, as well as high intake of fish, were inversely associated with advanced polyps (OR = 0.56, 95%CI: 0.36-0.87; OR = 0.63, 95%CI: 0.42-0.95; and OR = 0.66, 95%CI: 0.44-0.99, respectively), while only low intake of red meat was inversely associated with non-advanced adenomas (OR = 0.71, 95%CI: 0.49-0.97).

CONCLUSION:A better adherence to the MD, specifically low intake of sugar-sweetened beverages and red meat as well as high intake of fish, is related to lower odds for advanced polyps.

BACKGROUND:Evidence remains mixed on the benefits of oral cryotherapy in the prevention of oral mucositis and pain associated with fluorouracil-based chemotherapy.

OBJECTIVES:The intent of this article is to evaluate the effect of oral cryotherapy on the prevention of oral mucositis and pain among patients with colorectal cancer undergoing fluorouracil-based chemotherapy.

METHODS:Using an experimental study design, the authors randomly assigned 80 patients to either the intervention (n = 40) or usual care group (n = 40). Intervention group participants received oral cryotherapy in the form of ice chips held in their mouths during chemotherapy infusion. Both groups used sodium bicarbonate mouthwash postchemotherapy until the next cycle.

FINDINGS:In the usual care group, most participants reported grade 2 (moderate to life-threatening) or greater mucositis. Pain associated with mucositis was lower using oral cryotherapy, with the majority of participants in the intervention group reporting no pain.

PURPOSE:Physically active individuals have a lower risk of developing colorectal cancer but the influence of exercise on cancer survival is unknown.

PATIENTS AND METHODS:By a prospective, observational study of 573 women with stage I to III colorectal cancer, we studied colorectal cancer-specific and overall mortality according to predefined physical activity categories before and after diagnosis and by change in activity after diagnosis. To minimize bias by occult recurrences, we excluded women who died within 6 months of their postdiagnosis physical activity assessment.

RESULTS:Increasing levels of exercise after diagnosis of nonmetastatic colorectal cancer reduced cancer-specific mortality (P for trend = .008) and overall mortality (P for trend = .003). Compared with women who engaged in less than 3 metabolic equivalent task [MET] -hours per week of physical activity, those engaging in at least 18 MET-hours per week had an adjusted hazard ratio for colorectal cancer-specific mortality of 0.39 (95% CI, 0.18 to 0.82) and an adjusted hazard ratio for overall mortality of 0.43 (95% CI, 0.25 to 0.74). These results remained unchanged even after excluding women who died within 12 and 24 months of activity assessment. Prediagnosis physical activity was not predictive of mortality. Women who increased their activity (when comparing prediagnosis to postdiagnosis values) had a hazard ratio of 0.48 (95% CI, 0.24 to 0.97) for colorectal cancer deaths and a hazard ratio of 0.51 (95% CI, 0.30 to 0.85) for any-cause death, compared with those with no change in activity.

CONCLUSION:Recreational physical activity after the diagnosis of stages I to III colorectal cancer may reduce the risk of colorectal cancer-specific and overall mortality.

Singapore has experienced a marked increase in colorectal cancer incidence over the past 40 years. Evidence from prospective studies in Western Europe and the USA suggests that low physical activity and high amounts of sedentary time are associated with increased colorectal cancer risk. The aim of this study is to evaluate these relationships in an Asian population. The Singapore Chinese Health Study enrolled 63 257 adults between 1993 and 1998. At enrollment, participants reported past year physical activity and time spent sitting. Incident colorectal cancers (n=1994) were identified through 31 December 2014. Cox proportional hazards models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) adjusted for potential confounders. Any strenuous-vigorous or moderate physical activity was reported by 13.7 and 22.1% of the cohort, respectively. Strenuous-vigorous physical activity was associated with statistically significant reduced colorectal cancer risk (HR=0.85; 95% CI: 0.74-0.99 for ≥0.5 h/week vs. none), but moderate was not. In analysis stratified by time spent watching television, an inverse relationship between moderate physical activity and colorectal cancer risk (HR=0.86; 95% CI: 0.72-1.01 for ≥0.5 h/week vs. none) was observed for those who reported atleast 3 h/day sitting watching television (Pinteraction=0.042). Participation in strenuous-vigorous physical activity, such as jogging, swimming, or heavy manual labor, was associated with reduced colorectal cancer risk among Singapore Chinese. Further research on physical activity and sedentary behaviors, independently and in combination, and colorectal cancer risk in Asian populations is needed.

Physical activity (PA) and vitamin D are thought to affect colorectal cancer prognosis. The present study investigates associations between 25(OH)D3 and PA in prospectively followed colorectal cancer patients in the ColoCare study. At 6, 12, and 24 mo after surgery, patients donated a blood sample, wore an accelerometer for 10 consecutive days, and completed a PA questionnaire. Plasma 25-hydroxyvitamin D3 (25(OH)D3) levels were measured by high-performance liquid chromatography. We tested associations using partial correlations and multivariate linear regression analysis, adjusted for season, age, and body mass index. A total of 137 assessments of 25(OH)D3 levels and PA were conducted (58 at 6 mo, 51 at 12 mo, and 28 at 24 mo). More than 60% of the patients were vitamin D-deficient (25(OH)D3≤20 ng/ml), independent of study time point. At 6-mo follow-up, accelerometry-based vigorous and moderate-to-vigorous PAs were positively associated with 25(OH)D3 levels (P = 0.04; P = 0.006,). PA together with season was a significant predictor of elevated 25(OH)D3 levels. Our results suggest that the majority of colorectal cancer patients may suffer from vitamin D deficiency. Engaging in PA may be an effective approach to increase their 25(OH)D3 levels.