Malignant Colorectal Cancer Research Articles

Aktuelle Entwicklungen in der regionalen Behandlung von peritonealen und pleuralen Tumoren (inkl. HIPEC und HITOC)

The multimodal treatment of limited peritoneal metastases may improve prognosis in selected patients (pseudomyxoma peritonei, malignant peritoneal mesothelioma, colorectal, gastric and ovarian cancer) provided complete cytoreduction can be performed. Additive intraoperative hyperthermic intraperitoneal chemotherapy (HIPEC) is often performed. If the treatment is undertaken in experienced (and certified) centres, associated mortality is low. Intrapleural hyperthermic chemoperfusion (HITOC) can be performed in patients with pleural malignancies, mainly for malignant pleural mesothelioma or metastases from a thymoma. In single patients, pleural metastases from gastrointestinal malignancies might be an indication. Both therapies (HIPEC and HITOC) are complex and their exact role has to be defined within further prospective randomised trials.

Practical exploration and research of Watson for oncology clinical decision support system in real-world and localized practice.

e18304 Background: Watson for Oncology (WFO) is a cognitive computing system developed by the IBM and trained by Memorial Sloan Kettering Cancer Center to provide evidence-based treatment recommendation for cancer patients. This study is to explore the impact on clinical treatment decision and patient communication based on the standard workflow we established of applying WFO in real-world clinical practice. Methods: From May 2018 to January 2019, 57 patients with advanced malignant tumors, including lung, breast, colorectal, gastric, esophageal, liver, ovarian and endometrial cancer, treated at Oncology Department of Beijing Chaoyang Integrative Medicine Emergency Medical Center were included in the study, of which 28 males and 29 females aged 29-89 years old. Treatment plan of each patient generated by WFO was compared with NCCN guidelines and Chinese local CSCO guidelines, and then evaluated and determined by MDT for final decision. Proportion of WFO recommendation fully or partially followed by clinicians was analyzed. Moreover, survey by questionnaire was conducted to collect feedback from these patients on their satisfaction of treatment and communication process. Results: Of all 57 patients enrolled, WFO’s options were highly concordant with NCCN guidelines and CSCO guidelines, and the finally adopted treatment plans after deliberately evaluated and discussed by MDT were 100% in the WFO recommended or for consideration category. Patient satisfaction and the compliance with instruction was significantly improved compared with historical data. Localization was most required in gastric, liver and esophageal cancer due to local drugs and therapies not available in WFO. Conclusions: This study verified that the artificial intelligent clinical decision supporting system can be applied in Chinese clinical practice to achieve high patient satisfaction and good efficacy. WFO meets Chinese and international standards for treatment, which will promote the standardized development of cancer treatment in China. Optimization, iteration, upgrading and localization are required for better practicability of WFO.

PCN152 AGE-ADJUSTED COLORECTAL CANCER INCIDENCE IN THE UNITIED STATES VERSUS SOUTH CAROLINA

The incidence of colorectal cancer (CRC) has declined in recent years for people of all races/ethnicities; however, the incidence of invasive CRC is increasing in younger adults. Our primary objective was to compare age-adjusted incidence of early- and late-onset CRC among SC residents to overall US estimates. Incident cases of CRC from January 1, 2001 through December 31, 2015 were retrieved from the National Program of Cancer Registries and NCI’s Surveillance, Epidemiology, and End Results (SEER) program using SEER*Stat. Incidence rates were calculated as five-year moving averages based upon age at CRC onset (early, 0-49 years; late, 50+ years) among SC and the entire US population. Subgroup analyses by sex/race classification were performed. Rates were expressed per 100,000 and age-adjusted to the 2000 US census standard population (19 age groups). A rate ratio (RR) and corresponding p-value were calculated for comparisons between SC and US. A 95% confidence interval was calculated for rates and ratios according to the methodology developed by Tiwari. A total of 2,160,038 malignant CRC cases were recorded in the US, including 32,585 cases in SC. A consistent trend of increased EOCRC incidence was observed in SC, 8.2 vs. 6.4 (RR2001-2015 1.28; 95% CI 1.21-1.36) and 8.1 vs. 7.4 (RR2011-2015 1.10; 95% CI 1.04-1.16). In the subgroup analysis, EOCRC incidence was significantly increased among all Whites, White males, and all males in SC during 2011-2015. Conversely, late-onset CRC has declined in both SC, from 171.6 to 114.6, and the US, from 170.3 to 120.4, during the study period. However, we observed a trend towards lower incidence in SC since 2004-2008 (RR2011-2015 0.95; 95% CI 0.93-0.97). Contrasting incidence rates were observed between the US and SC for both early- and late-onset CRC. This variance may represent differences in populations, screening, or risk factor exposure.

Oncologic Outcomes of Self-Expandable Metallic Stent as a Bridge to Surgery and Safety and Feasibility of Minimally Invasive Surgery for Acute Malignant Colonic Obstruction.

Although self-expandable metal stents (SEMS) are widely used as a bridge to surgery (BTS) in patients with malignant colorectal cancer obstruction, there has been some debate about their effect on long-term oncological outcomes. Furthermore, data on the safety and feasibility of minimally invasive surgery (MIS) combined with stent placement are scarce. We aimed to determine the long-term oncological outcomes of SEMS as a BTS, and the short-term outcomes of SEMS used with minimally invasive colorectal surgery. Data from patients who were admitted with malignant obstructing colon cancer between January 2006 and December 2015 were retrospectively reviewed; 71 patients underwent direct surgery and 182 patients underwent SEMS placement as a BTS. Long-term and short-term outcomes of the groups were compared. In a subgroup analysis of the BTS group, the short-term outcomes of conventional open surgery and MIS were compared. There were no differences in long-term oncologic outcomes between groups. The primary anastomosis rate was higher in the stent group than in the direct surgery group. In the stent group, postoperative complication rates were lower in the minimally invasive group than in the open surgery group. Time to flatus and time to soft diet resumption were shorter in the minimally invasive group, as was length of hospital stay. Elective surgery after stent insertion does not adversely affect long-term oncologic outcomes. Furthermore, MIS combined with stent insertion for malignant colonic obstruction is safe and feasible.

Prise en charge des patients atteints de métastases cérébrales de mélanome

Partitioning defective 3-like protein (Par3L) is a recently identified cell polarity protein that plays an important role in mammary stem cell maintenance. Previously, we showed that high expression of Par3L is associated with poor survival in malignant colorectal cancer (CRC), but the underlying mechanism remained unknown. To this end, we established a Par3L knockout colorectal cancer cell line using the CRISPR/Cas system. Interestingly, reduced proliferation, enhanced cell death and caspase-3 activation were observed in Par3L knockout (KO) cells as compared with wildtype (WT) cells. Consistent with previous studies, we showed that Par3L interacts with a tumor suppressor protein liver kinase B1 (Lkb1). Moreover, Par3L depletion resulted in abnormal activation of Lkb1/AMPK signaling cascade. Knockdown of Lkb1 in these cells could significantly reduce AMPK activity and partially rescue cell death caused by Par3L knockdown. Furthermore, we showed that Par3L KO cells were more sensitive to chemotherapies and irradiation. Together, these results suggest that Par3L is essential for colorectal cancer cell survival by inhibiting Lkb1/AMPK signaling pathway, and is a putative therapeutic target for CRC.

A Comparison Study among Several Tumor Markers in Serum Samples of Patients with Colon Cancers

During six years ago, 109 patients with malignant colon cancers at metastasis stages (II to IV stages), 112 patients “as a pathological control group”, and 85 healthy individuals were enrolled in the present work. CLEC4E, CEA, CA 19-9, and Serotonin levels were measured in the sera of study individuals using sandwich ELISA technique. Current study demonstrated significant increase in the levels of CLEC4E, CEA, and CA 19-9 in the malignant colorectal cancers comparison to pathological controls as well as healthy individuals. Serotonin levels were seemed to be lower at cancerous patients comparison to healthy controls. CLEC4E may be used as a definitive diagnostic marker for cancers than other nonmalignant diseases, moreover CLEC4E and serotonin can be considered as new diagnostic tools for colon cancer and are highly effective follow-up tools and can be diagnostic and follow-up tools when measured with other resident parameters. Measured parameters (CLEC4E, CEA, CA19-9, and Serotonin) can be effective screening tools when diagnosing tumor infections in the colon.

MicroRNA-769 is downregulated in colorectal cancer and inhibits cancer progression by directly targeting cyclin-dependent kinase 1.

BackgroundIn recent years, microRNAs (miRNAs) have been reported to be aberrantly expressed in colorectal cancer (CRC). The deregulation of miRNAs is implicated in the formation and progression of CRC, and participates in the regulation of a wide range of biological behaviors. Considering the crucial role of miRNAs in CRC, miRNAs are thought to have significant promise in the diagnosis and therapy of patients with this malignancy.Material and methodsReverse transcription-quantitative polymerase chain reaction (RT-qPCR) was performed to detect miR-769 expression in CRC tissues and cell lines. MTT assay and flow cytometry analysis were used to determine the effects of miR-769 upregulation in CRC cell proliferation and apoptosis, respectively. The influence of miR-769 overexpression in CRC cell migration and invasion was evaluated through migration and invasion assays. Notably, the possible mechanisms underlying the action of miR-769 in CRC cells were explored.ResultsIn the present study, miR-769 was frequently found to be poorly expressed in CRC tissues and cell lines. Functional assays showed that recovery of miR-769 expression suppressed CRC cell proliferation, migration, and invasion, increased cell apoptosis in vitro, and inhibited tumor growth in vivo. Cyclin-dependent kinase 1 (CDK1) was the direct target of miR-769 in CRC cells. CDK1 was overexpressed in CRC tissue samples and negatively correlated with miR-769 expression. In addition, CDK1 inhibition imitated the tumor suppressor activity of miR-769 in CRC cells, and restoration of CDK1 expression partially abolished the tumor-suppressing roles of miR-769 in malignant CRC cells.ConclusionThe results of this study demonstrated that miR-769 was downregulated in CRC and directly targeted CDK1 to be implicated in the regulation of CRC cell proliferation, apoptosis, migration and invasion. Thus, the miR-769/CDK1 axis might be an effective therapeutic target for treating patients with CRC.

FLYWCH1, a Novel Suppressor of Nuclear β-Catenin, Regulates Migration and Morphology in Colorectal Cancer.

Wnt/β-catenin signaling plays a critical role during development of both normal and malignant colorectal cancer tissues. Phosphorylation of β-catenin protein alters its trafficking and function. Such conventional allosteric regulation usually involves a highly specialized set of molecular interactions, which may specifically turn on a particular cell phenotype. This study identifies a novel transcription modulator with an FLYWCH/Zn-finger DNA-binding domain, called "FLYWCH1." Using a modified yeast-2-hybrid based Ras-Recruitment system, it is demonstrated that FLYWCH1 directly binds to unphosphorylated (nuclear) β-catenin efficiently suppressing the transcriptional activity of Wnt/β-catenin signaling that cannot be rescued by TCF4. FLYWCH1 rearranges the transcriptional activity of β-catenin/TCF4 to selectively block the expression of specific downstream genes associated with colorectal cancer cell migration and morphology, including ZEB1, EPHA4, and E-cadherin. Accordingly, overexpression of FLYWCH1 reduces cell motility and increases cell attachment. The expression of FLYWCH1 negatively correlates with the expression level of ZEB1 and EPHA4 in normal versus primary and metastatic colorectal cancer tissues in patients. Thus, FLYWCH1 antagonizes β-catenin/TCF4 signaling during cell polarity/migration in colorectal cancer. IMPLICATIONS: This study uncovers a new molecular mechanism by which FLYWCH1 with a possible tumor suppressive role represses β-catenin-induced ZEB1 and increases cadherin-mediated cell attachment preventing colorectal cancer metastasis.

The anti-cancer effect of retinoic acid signaling in CRC occurs via decreased growth of ALDH+ colon cancer stem cells and increased differentiation of stem cells.

BackgroundTumorigenesis is driven by stem cell (SC) overpopulation. Because ALDH is both a marker for SCs in many tissues and a key enzyme in retinoid acid (RA) signaling, we studied RA signaling in normal and malignant colonic SCs.HypothesisRA signaling regulates growth and differentiation of ALDH+ colonic SCs; dysregulation of RA signaling contributes to SC overpopulation and colorectal cancer (CRC) development.MethodsWe analyzed normal and malignant colonic tissues and CRC cell lines to see if retinoid receptors (RXR & RAR) are exclusively expressed in ALDH+ SCs, and if RA signaling changes during CRC development. We determined whether RA signaling regulates cancer SC (CSC) proliferation, differentiation, sphere formation, and population size.ResultsRXR & RAR were expressed in ALDH+ colonic SCs, but not in MCM2+ proliferative cells. Western blotting/immunostaining of CRCs revealed that RA signaling components become overexpressed in parallel with ALDH overexpression, which coincides with the known overpopulation of ALDH+ SCs that occurs during, and drives, CRC development. Treatment of SCs with all-trans retinoic acid (ATRA) decreased proliferation, sphere formation and ALDH+ SC population size, and induced differentiation along the neuroendocrine cell (NEC) lineage.ConclusionsRetinoid signaling, by regulating ALDH+ colonic CSCs, decreases SC proliferation, sphere formation, and population size, and increases SC differentiation to NECs. Dysregulation of RA signaling in colonic SCs likely contributes to overpopulation of ALDH+ SCs and CRC growth.ImplicationsThat retinoid receptors RXR and RAR are selectively expressed in ALDH+ SCs indicates RA signaling mainly occurs via ALDH+ SCs, which provides a mechanism to selectively target CSCs.

Non-participation in breast cancer screening among previous cancer patients

PurposeBreast cancer can be detected at early stages through organised screening. This study explored reasons for non-participation in breast cancer screening among previous cancer patients, who have high risk of developing a new primary cancer.MethodWe conducted a population-based historical cohort study, including all women invited to the first organised screening round in 2008–2009 in the Central Denmark Region (n = 149,234). All data were based on national registers.ResultsAmong women with previous cancer (n = 6638), 25.3% did not participate in breast cancer screening compared to 20.9% of women with no registrations of previous cancer, thus previous cancer patients were 21% less likely not to participate in breast cancer screening (PRR 1.21, 95% CI 1.16–1.27). Further analysis showed that this association was due to women receiving current cancer treatment or being in palliative care in the time leading up to screening. Women with previous malignant melanoma or colorectal cancer were more likely to participate in breast cancer screening, whereas women with previous gynaecological or “other” cancer types were less likely to participate.ConclusionScreening for breast cancer may help diagnose breast cancer at an early stage. Women with previous cancer who are not undergoing current treatment or in palliative care have the same propensity to participate as other women invited to breast cancer screening. Women with previous gynaecological cancer were less likely to participate in breast cancer screening than women with other cancer types. These results may only be generalised to similar health care systems.

Differential Roles of Tumor Necrosis Factor Ligand Superfamily Members as Biomarkers in Pancreatic Cancer.

The tumor necrosis factor–related weak inducer of apoptosis (TWEAK) belongs to the tumor necrosis factor ligand superfamily, which was shown to play an important role in inflammatory and malignant gastrointestinal diseases, including colitis or colorectal cancer. However, in contrast to other members of the TNF ligand superfamily, its role as a biomarker in pancreatic cancer is currently unknown. We analyzed serum levels of A proliferation-inducing ligand (APRIL) and TWEAK in 134 patients with pancreatic cancer. Results were compared with 50 healthy controls and correlated with clinical data. Intratumoral expression of APRIL and TWEAK in pancreatic cancer was analysed using the datasets made available by the TCGA-LIHC project. APRIL serum levels were significantly elevated in patients with pancreatic cancer compared to healthy controls, which is in line with previous findings. Notably, the diagnostic accuracy of circulating APRIL levels was similar to CA19-9, an established tumor marker for pancreatic cancer. In contrast, serum concentrations of TWEAK were decreased in pancreatic cancer patients. Interestingly, no differences in TWEAK concentrations became apparent between different clinical subgroups of pancreatic cancer. Moreover, within our cohort of patients, TWEAK levels did not correlate with the patients’ prognosis and the diagnostic as well as prognostic potential of TWEAK was lower than CA 19-9, when analyzed in this setting. Finally, using data from the TCGA-LIHC project, we demonstrate that expression levels of TWEAK and APRIL represent prognostic markers for patients’ survival according to Kaplan-Meier curve analyses. TWEAK and APRIL serum concentrations are regulated differently in patients with pancreatic cancer, highlighting diverse roles of variant TNF ligands in this type of cancer.

Evaluation of Colorectal Cancer Incidence Trends in the United States (2000-2014).

Colorectal cancer (CRC) incidence rates have declined in recent years for people of all races/ethnicities; however, the extent to which the decrease varies annually by demographic and disease-related characteristics is largely unknown. This study examines trends and annual percent change (APC) in the incidence among persons diagnosed with CRC in the United States of America from 2000–2014. The data obtained from the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) Program were analyzed, and all persons (N = 577,708) with malignant CRC recorded in the SEER 18 database from 2000 to 2014 were characterized according to sex, race, age at diagnosis, disease site and stage. Incidence rates and APC were calculated for the entire study period. Overall, the incidence rate of CRC decreased from 54.5 in 2000 to 38.6 per 100,000 in 2014, with APC = −2.66 (p < 0.0001). Decline in rates was most profound between 2008 and 2011 from 46.0 to 40.7 per 100,000 (APC = −4.04; p < 0.0001). Rates were higher for males (vs. females; rate ratio (RR) = 1.33) and for blacks (vs. whites; RR = 1.23). Proximal colon cancers at the localized stage were the predominant cancers. An increase in rate was observed among people younger than 50 years (6.6 per 100,000, APC= 1.5). The annual rate of CRC has decreased over time. However, the development and implementation of interventions that further reduce the disparities among demographic and disease-related subgroups are warranted.

NCOA5 promotes proliferation, migration and invasion of colorectal cancer cells via activation of PI3K/AKT pathway.

The nuclear receptor coactivator 5 (NCOA5) displays both coactivator and corepressor functions. Previous studies showed that alteration of NCOA5 participates in carcinogenesis and progression. However, its roles in colorectal cancer (CRC) remain unknown. Herein, we demonstrated that expression of NCOA5 in human CRC tissues was notably higher than that in adjacent tissues, which significantly correlated with clinicopathological features such as length of tumor, regional lymph node staging and cancer staging. Knockdown of NCOA5 markedly suppressed proliferation, migration and invasion of SW620 high malignant CRC cells. Silencing of NCOA5 also inhibited in vivo growth of SW620 CRC subcutaneously xenografted tumors in athymic BALB/c nude mice. Meanwhile, Overexpression of NCOA5 facilitated these processes in SW480 low malignant CRC cells. Furthermore, knockdown of NCOA5 induced cell cycle G1 phase arrest in SW620 cells, whereas overexpression of NCOA5 promoted G1 to S phase transition in SW480 cells. Mechanistic studies revealed that NCOA5 upregulated phospho-protein kinase B (p-PKB/AKT), Cyclin D1 and matrix metalloproteinase 9 (MMP9) as well as downregulated P27 in CRC cells. Notably, PI3K inhibitor LY294002 obviously attenuated the effects of NCOA5 on p-AKT, Cyclin D1, P27 and MMP9. Moreover, LY294002 and knockdown of Cyclin D1 or MMP9 remarkably blocked the tumor-promoting activity of NCOA5. Collectively, NCOA5 promoted CRC cell proliferation, migration and invasion by upregulating Cyclin D1 and MMP9 while downregulating P27 to a great extent via activating PI3K/AKT signaling pathway. These findings suggested that NCOA5 exhibits an oncogenic effect in human CRC and represents a novel therapeutic target for CRC.

Segmentation and classification of colon glands with deep convolutional neural networks and total variation regularization.

Segmentation of histopathology sections is a necessary preprocessing step for digital pathology. Due to the large variability of biological tissue, machine learning techniques have shown superior performance over conventional image processing methods. Here we present our deep neural network-based approach for segmentation and classification of glands in tissue of benign and malignant colorectal cancer, which was developed to participate in the GlaS@MICCAI2015 colon gland segmentation challenge. We use two distinct deep convolutional neural networks (CNN) for pixel-wise classification of Hematoxylin-Eosin stained images. While the first classifier separates glands from background, the second classifier identifies gland-separating structures. In a subsequent step, a figure-ground segmentation based on weighted total variation produces the final segmentation result by regularizing the CNN predictions. We present both quantitative and qualitative segmentation results on the recently released and publicly available Warwick-QU colon adenocarcinoma dataset associated with the GlaS@MICCAI2015 challenge and compare our approach to the simultaneously developed other approaches that participated in the same challenge. On two test sets, we demonstrate our segmentation performance and show that we achieve a tissue classification accuracy of 98% and 95%, making use of the inherent capability of our system to distinguish between benign and malignant tissue. Our results show that deep learning approaches can yield highly accurate and reproducible results for biomedical image analysis, with the potential to significantly improve the quality and speed of medical diagnoses.

Participation of CCL1 in Snail-Positive Fibroblasts in Colorectal Cancer Contribute to 5-Fluorouracil/Paclitaxel Chemoresistance.

PurposeCancer-associated fibroblasts (CAFs) activated by cancer cells has a central role in development and malignant biological behavior in colorectal cancer (CRC). Adult fibroblasts do not express Snail, but Snail-positive fibroblasts are discovered in the stroma of malignant CRC and reported to be the key role to chemoresistance. However, the reciprocal effect of CAFs expressed Snail to chemoresistance on CRC cells and the underlying molecular mechanisms are not fully characterized.Materials and MethodsSnail-overexpressed 3T3 stable cell lines were generated by lipidosome and CT26 mixed with 3T3-Snail subcutaneous transplanted CRC models were established by subcutaneous injection. Cell Counting Kit-8, flow cytometry and western blotting assays were performed, and immunohistochemistry staining was studied. The cytokines participated in chemoresistance was validated with reverse transcriptase-polymerase chain reaction and heatmap.ResultsSnail-expression fibroblasts are discovered in human and mouse spontaneous CRCs. Overexpression of Snail induces 3T3 fibroblasts transdifferentiation to CAFs. CT26 co-cultured with 3T3-Snail resisted the impairment from 5-fluorouracil and paclitaxel in vitro. The subcutaneous transplanted tumor models included 3T3-Snail cells develop without restrictions even after treating with 5-fluorouracil or paclitaxel. Moreover, these chemoresistant processes may be mediated by CCL1 secreted by Snail-expression fibroblasts via transforming growth factor β/nuclear factor-κB signaling pathways.ConclusionTaken together, Snail-expressing 3T3 fibroblasts display CAFs properties that support 5-fluorouracil and paclitaxel chemoresistance in CRC via participation of CCL1 and suggest that inhibition of the Snail-expression fibroblasts in tumor may be a useful strategy to limit chemoresistance.

Clinical performance evaluation of the Idylla NRAS-BRAF mutation test on retrospectively collected formalin-fixed paraffin-embedded colorectal cancer tissue

AimsUnderstanding the molecular mechanisms of underlying disease has led to a movement away from the one-drug-fits-all paradigm towards treatment tailored to the genetic profile of the patient. The Biocartis Idylla...

Research progress on circadian clock genes in common abdominal malignant tumors.

The circadian clock refers to the inherent biological rhythm of an organism, which, is accurately regulated by numerous clock genes. Studies in recent years have reported that the abnormal expression of clock genes is ubiquitous in common abdominal malignant tumors, including liver, colorectal, gastric and pancreatic cancer. In addition, the abnormal expression of certain clock genes is closely associated with clinical tumor parameters or patient prognosis. Studies in clock genes may expand the knowledge about the mechanism of occurrence and development of tumors, and may provide a new approach for tumor therapy. The present study summarizes the research progress in this field.

Immunohistochemical Study of HER2/neu Expression in Colorectal Cancer and its Relation to other Clinicopathological Criteria and Prognostic Factors

Background: Human epidermal growth factor receptor 2 (HER2) overexpression and amplification have been studied as a therapeutic and prognostic target in a number of tumors although conflicting data exist about the incidence and clinical consequence of HER2/neu status in the patients with colorectal cancer. The aim of the present study was to evaluate the immunohistochemical expression of HER2/neu and its relationship with clinicopathological parameters and prognostic factors. Methods: This study involved 50 specimens of malignant colorectal cancer lesions and HER-2/neu expression was evaluated by the Hercep-Test Kit. Results: Out of 50 cases, most of them (76%) were HER2/neu negative and in 12 (24%) cases, HER2/neu positive immunostaining were detected. 24% (n = 12), 36% (n = 18), 30% (n = 15), and 10% (n = 5) were scored as 3+, 2+, 1+, and 0 respectively. No significant association was noted between HER-2/neu expression and patients’ age, tumor size, gender, location, grade and stage (P > 0.05). Conclusions: The immunohistochemical evaluation of HER2/neu overexpression for potential targeted anti-HER2 therapy may not be valuable for the patients with colorectal cancer and also studies with larger sample sizes using standardized tests are needed to understand the exact biologic role of HER-2/neu in this type of tumor.

TrkC promotes colorectal cancer growth and metastasis.

The current work reveals that TrkC receptor is crucial to many aspects of tumorigenicity and metastasis of cancer. However, with only a few exceptions, such as colorectal cancer (CRC), where suppressing tumorigenic and metastatic ability via expression of TrkC as tumor suppressor have been proposed. These diverse lines of evidence led us to investigate whether TrkC is involved in CRC progression. By using mouse models and molecular biology analyses, we demonstrate that TrkC acts as an activator in tumorigenicity and metastasis of colorectal cancer. In this study, TrkC was frequently overexpressed in CRC cells, patients’ tumor samples and an azoxymethane/dextran sulphate sodium-induced mouse model of colitis-associated CRCs. TrkC expression was associated with a high-grade CRC phenotype, leading to significantly poorer survival. Also, TrkC expression promoted the acquisition of motility and invasiveness in CRC. Moreover, TrkC increased the ability to form tumor spheroids, a property associated with cancer stem cells. Importantly, knockdown of TrkC in malignant mouse or human CRC cells inhibited tumor growth and metastasis in a mouse xenograft model. Furthermore, TrkC enhanced metastatic potential and induced proliferation by aberrant gain of AKT activation and suppression of transforming growth factor (TGF)-β signalling. Interestingly, TrkC not only modulated the actions of TGF-β type II receptor, but also attenuated expression of this receptor. These findings reveal an unexpected physiological role of TrkC in the pathogenesis of CRC. Therefore, TrkC is a potential target for designing effective therapeutic strategies for CRC development.

High expression of partitioning defective 3-like protein is associated with malignancy in colorectal cancer.

Partitioning defective 3-like protein is a novel cell polarity protein. Recently, partitioning defective 3-like protein has been demonstrated with tumor-promoting function by disrupting tight junction, inhibiting tumor suppressor liver kinase B1, and maintaining mammary stem cells. For the first time, we studied partitioning defective 3-like protein expression in malignant colorectal cancer. We used immunohistochemistry scoring system to evaluate partitioning defective 3-like protein expression in 196 colorectal cancer tissues and 33 adjacent normal tissues. We found that colorectal cancer tissues had much stronger partitioning defective 3-like protein immunoreactivity than normal tissues, and colorectal cancer patients with positive partitioning defective 3-like protein expression were characterized with higher cancer stages, metastasis, poor tumor differentiation, larger tumor size, as well as high levels of colorectal cancer markers carcinoembryonic antigen and cancer antigen 19-9. Besides, partitioning defective 3-like protein overexpression was independently predictive of lower survival rate in colorectal cancer patients, even after adjusting the influence of cofactors. Moreover, we also found that partitioning defective 3-like protein was associated with rapid growing colorectal cancer, while knockdown of partitioning defective 3-like protein expression largely inhibited cancer cell proliferation. Our study provided the first evidence that partitioning defective 3-like protein was overexpressed in colorectal cancer and associated with disease malignancy. Also, partitioning defective 3-like protein may serve as a promising prognostic marker and a potential therapeutic target for colorectal cancer treatment. Further study is necessary to understand the regulatory mechanism of partitioning defective 3-like protein in colorectal cancer and the feasibility of its application in clinic.