5-Fluorouracil enteric-coated nanoparticles for improved apoptotic activity and therapeutic index in treating colorectal cancer

Gastrointestinal (GI) motility disorders in type 2 diabetes mellitus (T2DM) are common. However, the endpoints in well-controlled T2DM in elderly patients are barely understood. To evaluate GI transit and gastric myoelectric activity in elderly patients with T2DM who were undergoing treatment with metformin and to compare them with non-diabetic healthy controls. A total of thirty participants were enrolled in this study: young non-diabetic (n=10), elderly non-diabetic controls (n=10), and patients with T2DM managed with metformin (n=10). After fasting overnight, the participants ingested a standard meal and magnetic markers for non-invasive monitoring of GI transit and gastric contractility using the alternating current biosusceptometry and electrogastrography techniques. Mean gastric emptying time, mean colon arrival time, and mean intestinal transit time were determined. There were no significant differences between the groups and in the parameters evaluated (P>0.05). The frequency and amplitude of gastric myoelectric activity were not different between groups; however, abnormal rhythmic index and the half-bandwidth were slightly higher for both elderly diabetic and non-diabetic groups compared with the young adults (P<0.01 and P<0.05, respectively). Our study showed unaltered gastric emptying and intestinal transit in T2DM patients with good glycemic control, and suggest changes in the gastric electrical activity can be a part of aging.

KRas mutations are frequently seen in solid tumors such as lung (~25%), colorectal (~40%) and pancreatic (~90%) cancers. The G12C mutation accounts for ~50% of all KRas mutations in lung cancer and to a lower percentage in other tumor types. Recently, selective inhibitors targeting the KRas-G12C mutation through covalent link to the cysteine of the mutated protein have been advanced to early clinical development and exhibited encouraging response in patients with lung cancer. Here, we present a novel small molecule compound that specifically inhibits KRas-G12C in vitro (cell lines) and in vivo (cell line-derived xenograft tumor models). The anti-tumor activity of D-1553 is evaluated across a panel of cancer cell lines including lung, pancreatic and colorectal cancers and shown to be active only in cancer cells with KRas-G12C mutation. In addition, D-1553 is highly potent in vivo in various cell line-derived xenograft tumor models with KRas-G12C mutation as a single agent. When D-1553 is combined with MEK inhibitor, SHP2 inhibitor or cytotoxic agents, further tumor growth inhibition or regression was observed in tumor xenograft models. These data suggest that D-1553 has anti-tumor activity in a broad spectrum of cancers and is suitable for tissue-agnostic clinical development targeting cancers with KRas-G12C mutation. D-1553 is currently in a Phase 1/2 clinical trial evaluating safety, tolerability, PK and efficacy in patients with advanced solid tumors harboring KRasG12C mutation (NCT04585035). Citation Format: Zhe Shi, Jifang Weng, Xiaochong Fan, Emma Wang, Qingqing Zhu, Liangshan Tao, Zixing Han, Zhenwu Wang, Haotao Niu, Yueheng Jiang, Ling Zhang, Xing Dai, Yaolin Wang. Discovery of D-1553, a novel and selective KRas-G12C Inhibitor with potent anti-tumor activity in a broad spectrum of tumor cell lines and xenograft models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 932.

The Host Inflammatory Response Promotes Liver Metastasis by Increasing Tumor Cell Arrest and Extravasation

Chrysopogon zizanioides (L.) Roberty (vetiver) is a perennial medicinal grass with deep aromatic roots traditionally used for several ailments. Its root essential oil (CZEO) is rich in phytochemicals with documented antimicrobial, anti-inflammatory, and antioxidant activities. Although its anticancer potential remains underexplored, the complex phytochemical profile of CZEO positions it as a promising multi-target therapy, particularly for colorectal (CRC) and lung cancers where resistance and pathway redundancy often limit conventional treatments. Therefore, this study aimed to investigate the phytochemical composition and antiproliferative activity of CZEO from Qatar against colorectal (HCT-116) and lung (A549) cancer cells and to elucidate its molecular targets and mechanisms of action in CRC and lung cancer using network pharmacology and in silico approaches. CZEO was extracted by steam distillation and characterized using GC-MS. In vitro proliferation assays with HCT-116 colorectal and A549 lung cancer cells were conducted using the Alamar Blue assay. The ten most abundant phytochemicals identified by GC-MS were assessed for drug-likeness and ADMET properties and further analyzed through network pharmacology, molecular docking, and molecular dynamics (MD) simulations to elucidate the molecular targets and mechanisms underlying CZEO's anticancer activity. GC-MS profiling identified 40 compounds, predominantly sesquiterpenoids (93%), including khusimol, β-eudesmol, α-vetivone, and rosifoliol. CZEO inhibited cancer cell viability in a dose-dependent manner, with IC50 values of 62.95 ± 2.19 µg/mL for HCT-116 and 167.82 ± 6.51 µg/mL for A549 cells, demonstrating greater potency against colorectal cancer. CZEO did not affect the growth of normal human neonatal fibroblasts (HDFn), suggesting potential selectivity for cancerous cells. ADMET predictions indicated favorable pharmacokinetics and low toxicity of CZEO's top 10 abundant compounds (TACs). Network pharmacology revealed 373 and 394 overlapping gene targets between TACs and lung and colorectal cancer, respectively. The overlapping genes were used to construct a protein-protein interaction (PPI) network to identify hub genes. STAT3 and AKT1 consistently emerged as common top-scoring hub genes in both cancers. Molecular docking of TACs showed strong binding affinities of rosifoliol and α-vetivone to AKT1 (-6.20 and -5.93 kcal/mol, respectively) and STAT3 (-5.19 and -5.09 kcal/mol, respectively), surpassing reference inhibitors. MD simulations confirmed stable ligand-protein interactions and structural stabilization, particularly with α-vetivone. CZEO from Qatar exhibits potent antiproliferative activity against colorectal and lung cancer cells, supported by a sesquiterpenoid-rich phytochemical profile. Integrative computational analyses highlight AKT1 and STAT3 as key molecular targets, with rosifoliol and α-vetivone emerging as promising lead compounds. These findings support CZEO as a natural, multi-target anticancer agent, warranting further mechanistic and in vitro and in vivo validation.

BackgroundColorectal cancer (CRC) is third most commonly diagnosed cancer worldwide. The aim of the prospective study was to evaluate mitosis and apoptosis of epithelial cells at each stage of colorectal neoplasia.MethodsA total of 61 persons were enrolled into the study: 18 patients with non-advanced colorectal adenoma (non-a-A), 13 patients with advanced colorectal adenoma (a-A), 13 patients with CRC and 17 controls: individuals with normal findings on colonoscopy. Biopsy samples were taken from pathology (patients) and healthy mucosa (patients and healthy controls). Samples were formalin-fixed paraffin-embedded and stained with haematoxylin-eosin. Mitotic and apoptotic activity were evaluated in lower and upper part of the crypts and in the superficial compartment. Apoptotic activity was also assessed using detection of activated caspase-3.ResultsIn controls, mitotic activity was present in lower part of crypts, accompanied with low apoptotic activity. Mitotic and apoptotic activity decreased (to almost zero) in upper part of crypts. In superficial compartment, increase in apoptotic activity was observed. Transformation of healthy mucosa into non-a-A was associated with significant increase of mitotic activity in lower and upper part of the crypts and with significant increase of apoptotic activity in all three compartments; p < 0.05. Transformation of non-a-A into a-A did not lead to any further significant increase in apoptotic activity, but was related to significant increase in mitotic activity in upper part of crypts and superficial compartment. A significant decrease in apoptotic activity was detected in all three comparments of CRC samples compared to a-A; p < 0.05. No differences in mitotic and apoptotic activity between biopsies in healthy controls and biopsy samples from healthy mucosa in patients with colorectal neoplasia were observed. Detection of activated caspase-3 confirmed the above findings in apoptotic activity.ConclusionsSignificant dysregulation of mitosis and apoptosis during the progression of colorectal neoplasia, corresponding with histology, was confirmed. In patients with sporadic colorectal neoplasia, healthy mucosa does not display different mitotic and apoptotic activity compared to mucosa in healthy controls and therefore adequate endoscopic/surgical removal of colorectal neoplasia is sufficient.

Therapeutic effects of coptisine derivative EHLJ7 on colorectal cancer by inhibiting PI3K/AKT pathway

BackgroundAlloplex Biotherapeutics has developed a novel autologous cellular therapy for cancer that uses ENgineered Leukocyte ImmunoSTimulatory cell lines called ENLIST cells to activate and expand a heterogeneous population of tumor killing effector cells from human peripheral blood mononuclear cells (PBMCs). The 2-week manufacturing process from PBMCs consistently results 300-fold expansion of NK cells, CD8+ T cells, gamma/delta T cells, NKT cells and some CD4+ T cells, collectively called SUPLEXA therapeutic cells. SUPLEXA cells will be delivered back to cancer patients via intravenous administrations on a weekly schedule as an autologous adoptive cellular immunotherapy for cancer. In this study, we tested SUPLEXA cells developed from normal healthy volunteer PBMCs for their ability to infiltrate and kill patient-derived tumor organoids (PDO) as a pre-clinical assessment for potency against 2 different types of tumor organoids.MethodsTumor organoids derived from colorectal cancer (CRC) or non-small cell lung carcinoma (NSCLC) patients were labeled with cell-trace red dye and plated at equal density in a 96-well plate. After 3 days culture, SUPLEXA cells were thawed (82.8% viable), labeled with cell-trace violet dye, and added to PDO at 1:2 serial diluted numbers ranging from 2 million to 7,800 cells per well. Fluorescent images were captured at 24 hours after adding SUPLEXA cells to PDO models to measure PDO size, tumor infiltration, and PDO killing.ResultsAdding SUPLEXA cells to PDO from CRC and NSCLC resulted in significant infiltration and killing of organoids by 24 hours as shown by the fluorescent images and the organoid size plot for the CRC PDO model (figure 1). Significant reduction in PDO size was observed by adding 31,240 SUPLEXA cells. Similar results were observed with the NSCLC PDO model with significant reduction in PDO size by adding 15,600 SUPLEXA cells. Obvious organoid infiltration was observed in both PDO models and organoid fluorescence was significantly reduced by addition of SUPLEXA cells in both PDO models to suggest that SUPLEXA cells were able to reduce tumor burden (figure 2).Abstract 164 Figure 1CRC organoid infiltration and killing by SUPLEXA. A representative fluorescent image of CRC organoid killing with addition of increasing SUPLEXA cell numbers and a plot showing statistical analysis of 6 replicate wells for changes in CRC organoid size in relation to SUPLEXA cell number additionsAbstract 164 Figure 2Dose-dependent killing in CRC and NSCLC PDO models. CRC and NSCLC organoids were detected by total red fluorescence at 24 hours after adding the indicated numbers of SUPLEXA cells. Loss of red fluorescence after adding SUPLEXA is a measure of overall tumor cell killing/burden in organoids. Data is plotted as mean ± SEM for n=6 replicates per group.ConclusionsSUPLEXA cells infiltrated and killed tumor cells in patient-derived organoids within 24 hours of culture at low cell concentrations indicating potent tumor killing activity. The observed activity in both colorectal and lung cancer organoid models support broad anti-tumor killing activity by SUPLEXA. These results provide further evidence that PBMCs from cancer patients can be activated and expanded by our approach as a novel autologous cellular immunotherapy for cancer.

Anticancer effect of Cenchrus ciliaris L

Beta-Caryophyllene (BCP), a naturally occurring sesquiterpene abundantly found in cloves, hops, and cannabis, is the active candidate of a relatively new group of vascular-inhibiting compounds that aim to block existing tumor blood vessels. Previously, we have reported the anti-cancer properties of BCP by utilizing a series of in-vitro anti-tumor-related assays using human colorectal carcinoma cells. The present study aimed to investigate the effects of BCP on in-vitro, ex-vivo, and in-vivo models of anti-angiogenic assays and evaluate its anti-cancer activity in xenograft tumor (both ectopic and orthotopic) mice models of human colorectal cancer. Computational structural analysis and an apoptosis antibody array were also performed to understand the molecular players underlying this effect. BCP exhibited strong anti-angiogenic activity by blocking the migration of endothelial cells, tube-like network formation, suppression of vascular endothelial growth factor (VEGF) secretion from human umbilical vein endothelial cells and sprouting of rat aorta microvessels. BCP has a probable binding at Site#0 on the surface of VEGFR2. Moreover, BCP significantly deformed the vascularization architecture compared to the negative control in a chick embryo chorioallantoic membrane assay. BCP showed a remarkable reduction in tumor size and fluorescence molecular tomography signal intensity in all the mice treated with BCP, in a dose-dependent relationship, in ectopic and orthotopic tumor xenograft models, respectively. The histological analysis of the tumor from BCP-treated mice revealed a clear reduction of the density of vascularization. In addition, BCP induced apoptosis through downregulation of HSP60, HTRA, survivin, and XIAP, along with the upregulation of p21 expressions. These results suggest that BCP acts at multiple stages of angiogenesis and could be used as a promising therapeutic candidate to halt the growth of colorectal tumor cells.

Background: PI3K/Akt signaling pathway plays a key role in a series of cellular functions related to cell growth, proliferation, survival and differentiation. Dysregulation of the PI3K pathway is implicated in many human cancers. Thus we intended to discover novel pan-PI3K inhibitors to treat various solid tumors, such as colorectal cancer, gastric carcinoma, lung carcinoma and breast cancer, etc. Methods: We explored SAR based on a PI3K/mTOR dual inhibitor series to selectively improve the PI3K activity over that of mTOR. PI3Kα/mTOR enzymatic activity assays, MCF-7 cellular (p-AktS473) activity assay and mouse in vivo pharmacokinetic analyses were used to direct compound optimization. Compounds with superior in vitro activity and in vivo pharmacokinetic properties were then tested for in vivo antitumor efficacy in patient derived xenograft (PDX) tumor models. Results: WX008 was identified as a potent PI3K inhibitor with PI3Kα/mTOR IC50 of 0.07 nM/233 nM (selectivity 3328×) and superior MCF-7 cellular (p-AktS473) activity (IC50 of 5.91 nM). For its excellent pharmacokinetic properties WX008 was evaluated for in vivo antitumor efficacy. As results, WX008 displayed equivalent efficacy at much lower dose than BKM-120 in several PDX tumor models (Table 1). Table 1 In vivo efficacy of BKM-120 and WX008 Cmpd_IDBKM-120WX008CO-04-0032 PDX72% TGI @30 mpk86% TGI @8 mpkST-02-0013 PDX50% TGI @8 mpk 77% TGI @15 mpk53% TGI @4 mpk 90% TGI @8 mpkLU-01-0010 PDX74% TGI @30 mpk74% TGI @8 mpk Conclusions: WX008 is a novel potent pan-PI3K inhibitor with high selectivity over mTOR and inhibits tumor growth in several PDX tumor models. Citation Format: Tao Yu, Lingwei Kong, Yong Wang, Peipei Jiang, Zhe min Rong, Chang jun Wang, Jing jie Huang, Dan Yao, Yu xin Qin, Cheng de Wu, Shu hui Chen, Xin Tian, Fei Liu, Ping Dong, Zhi Lin Chen. Novel pan-PI3K inhibitor WX008 demonstrates significant antitumor efficacy in three xenograft tumor models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5453.

IntroductionDespite the existence of new therapeutic options, breast (BC) and colorectal (CC) cancers remain the leading causes of cancer death and the most commonly diagnosed in worldwide. Studies have reported that imidazole derivates show anticancer, antimicrobial, antibacterial, antifungal and antioxidant activities. Furthermore, recently it has been found that the association between imidazole ligands and copper increases their DNA binding affinity giving potential anticancer activity. Therefore, we synthesised three novel Cu(II) complexes using heterocyclic nitroimidazole derivatives as ligands. The aim of this study is to evaluate the cytotoxic activity of these complexes in two BC and two CC cell lines.Material and methodsNitroimidazole derived ligands containing cyclohexylamine, morpholine and piperidine and the respective Cu(II) complexes were synthesised. MCF-7, HCC1806, LS1034 and WiDr cell lines were cultured and grown in proper conditions. To evaluate the cytotoxic activity of these Cu(II) complexes on four cell lines, MTT colorimetric assay was used. Cells were seeded in 48 well-plates and then were treated with increasing concentrations of the complexes, from 0.5 to 200 µM. After 48 hour of incubation, medium was removed and MTT was added. Two hours later, isopropanol was added in order to dissolve formazan crystals. The absorbance was read at 570 and 620 nm and IC50 (half maximal inhibitory concentration) values determined.Results and discussionsSome Cu(II) complexes exhibit anticancer activity in cell lines. Studies show that for the MCF-7 and LS1034 cell lines, the nitroimidazole derived complex containing cyclohexylamine presents IC50 values of 22.2 and 23.9 µM, respectively. For WiDr cell line, the same complex has an IC50 of 50.5 µM. The best IC50 value (2.9 µM) for this complex occurs in the HCC1806 cell line, a chemoresistant BC cell line.Curiously, the complex containing piperidine presents a IC50 of 3.8 µM in HCC1806 cell line, while in the other BC cell line (MCF-7) there is no anticancer activity.The nitroimidazole derived complex containing cyclohexylamine is, consequently, the most promising compound in four cell lines.ConclusionCu(II) complexes derived from nitroimidazole presented anticancer activity against all cell lines. The complex containing cyclohexylamine revealed to be the most promising, especially in HCC1806, basaloid triple-negative breast cancer, known as therapy-resistant.

Background: The orchid plants of Dendrobium, belong to the largest family of flowering plants orchidaceae. The genus Dendrobium reported to possess various therapeutic activities including anticancer activity. In the present scenario, cancer is one of the most leading causes of death worldwide. Therefore, the main objective of the present study was to demonstrate the cytotoxic and apoptotic inducing activity of Dendrobium crepidatum and Dendrobium chrysanthum ethanolic extracts in T-cell lymphoma. Methods: MTT assay was done to evaluate the cytotoxic effect of the extracts on lymphoma cells. The reactive oxygen species (ROS) generation by the ethanolic extracts was also examined by DCFH-DA. Fluorescence microscopy studies and DNA fragmentation assay were done to investigate the apoptotic cell death. Flow cytometry was done to check the effect of ethanolic extracts on cell cycle phase distribution. Results: The results revealed that both the extracts led to dose dependent cytotoxic effect in T-cell lymphoma along with increased generation of intracellular reactive oxygen species in a dose and time dependent manner. The fluorescent microscopic studies showed that the extracts induced cellular shrinkage, chromatin condensation and nuclear fragmentation, the major hallmarks of apoptosis, in dose dependent manner. The presence of DNA ladder further confirms the process of nuclear fragmentation, and the cell cycle analysis showed significant delay at G2/M phase of the cell cycle with both the extracts. Conclusion: The whole study suggests that Dendrobium crepidatum and Dendrobium chrysanthum ethanolic extracts induced substantial cytotoxic and apoptotic activity in T-cell lymphoma. Therefore, further studies are needed to establish the detailed mechanism of anticancer activity of both the ethanolic extracts.

&lt;div&gt;Abstract&lt;p&gt;&lt;b&gt;Purpose:&lt;/b&gt; &lt;i&gt;BATF2&lt;/i&gt;, a novel IFN-stimulated gene, inhibits tumor cell proliferation, invasion, and migration. The objectives of this study were to determine how BATF2 expression is associated with colorectal cancer progression and patient outcome, to investigate how BATF2 overexpression inhibits hepatocyte growth factor (HGF)/MET signaling, and to elucidate the rationale for combining MET inhibitors with IFN.&lt;/p&gt;&lt;p&gt;&lt;b&gt;Experimental Design:&lt;/b&gt; BATF2 expression in colorectal cancer tissues was determined and correlated with colorectal cancer patient prognosis. Cultured colorectal cancer cells were used to investigate the effects of BATF2 overexpression on the malignant phenotype of colorectal cancer cells and HGF/MET signaling. Tumor xenograft models were used to validate the effects of BATF2 on colorectal cancer xenograft growth and assess the efficacy of the combination of MET inhibitors with IFNs in colorectal cancer.&lt;/p&gt;&lt;p&gt;&lt;b&gt;Results:&lt;/b&gt; In colorectal cancer tissues, BATF2 was found to be significantly downregulated, and its expression negatively correlated with MET expression. Decreased BATF2 expression was associated with progression and shorter patient survival in colorectal cancer. BATF2 overexpression promoted apoptosis and inhibited proliferation, migration, and invasion in colorectal cancer cells, as well as dramatically blunted tumor xenograft growth. In addition, MET inhibitors in combination with IFNβ produced synergistic cytotoxicity both &lt;i&gt;in vitro&lt;/i&gt; and &lt;i&gt;in vivo&lt;/i&gt;.&lt;/p&gt;&lt;p&gt;&lt;b&gt;Conclusions:&lt;/b&gt; Together, these novel findings suggest that &lt;i&gt;BATF2&lt;/i&gt;, a tumor suppressor gene, is a potent negative regulator of HGF/MET signaling in colorectal cancer and may serve as a prognostic tumor marker. Furthermore, these results provide a rationale for combining MET inhibitors with IFNs in preclinical trials. &lt;i&gt;Clin Cancer Res; 21(7); 1752–63. ©2015 AACR&lt;/i&gt;.&lt;/p&gt;&lt;/div&gt;

BATF2, a novel IFN-stimulated gene, inhibits tumor cell proliferation, invasion, and migration. The objectives of this study were to determine how BATF2 expression is associated with colorectal cancer progression and patient outcome, to investigate how BATF2 overexpression inhibits hepatocyte growth factor (HGF)/MET signaling, and to elucidate the rationale for combining MET inhibitors with IFN. BATF2 expression in colorectal cancer tissues was determined and correlated with colorectal cancer patient prognosis. Cultured colorectal cancer cells were used to investigate the effects of BATF2 overexpression on the malignant phenotype of colorectal cancer cells and HGF/MET signaling. Tumor xenograft models were used to validate the effects of BATF2 on colorectal cancer xenograft growth and assess the efficacy of the combination of MET inhibitors with IFNs in colorectal cancer. In colorectal cancer tissues, BATF2 was found to be significantly downregulated, and its expression negatively correlated with MET expression. Decreased BATF2 expression was associated with progression and shorter patient survival in colorectal cancer. BATF2 overexpression promoted apoptosis and inhibited proliferation, migration, and invasion in colorectal cancer cells, as well as dramatically blunted tumor xenograft growth. In addition, MET inhibitors in combination with IFNβ produced synergistic cytotoxicity both in vitro and in vivo. Together, these novel findings suggest that BATF2, a tumor suppressor gene, is a potent negative regulator of HGF/MET signaling in colorectal cancer and may serve as a prognostic tumor marker. Furthermore, these results provide a rationale for combining MET inhibitors with IFNs in preclinical trials.

&lt;div&gt;Abstract&lt;p&gt;&lt;b&gt;Purpose:&lt;/b&gt; &lt;i&gt;BATF2&lt;/i&gt;, a novel IFN-stimulated gene, inhibits tumor cell proliferation, invasion, and migration. The objectives of this study were to determine how BATF2 expression is associated with colorectal cancer progression and patient outcome, to investigate how BATF2 overexpression inhibits hepatocyte growth factor (HGF)/MET signaling, and to elucidate the rationale for combining MET inhibitors with IFN.&lt;/p&gt;&lt;p&gt;&lt;b&gt;Experimental Design:&lt;/b&gt; BATF2 expression in colorectal cancer tissues was determined and correlated with colorectal cancer patient prognosis. Cultured colorectal cancer cells were used to investigate the effects of BATF2 overexpression on the malignant phenotype of colorectal cancer cells and HGF/MET signaling. Tumor xenograft models were used to validate the effects of BATF2 on colorectal cancer xenograft growth and assess the efficacy of the combination of MET inhibitors with IFNs in colorectal cancer.&lt;/p&gt;&lt;p&gt;&lt;b&gt;Results:&lt;/b&gt; In colorectal cancer tissues, BATF2 was found to be significantly downregulated, and its expression negatively correlated with MET expression. Decreased BATF2 expression was associated with progression and shorter patient survival in colorectal cancer. BATF2 overexpression promoted apoptosis and inhibited proliferation, migration, and invasion in colorectal cancer cells, as well as dramatically blunted tumor xenograft growth. In addition, MET inhibitors in combination with IFNβ produced synergistic cytotoxicity both &lt;i&gt;in vitro&lt;/i&gt; and &lt;i&gt;in vivo&lt;/i&gt;.&lt;/p&gt;&lt;p&gt;&lt;b&gt;Conclusions:&lt;/b&gt; Together, these novel findings suggest that &lt;i&gt;BATF2&lt;/i&gt;, a tumor suppressor gene, is a potent negative regulator of HGF/MET signaling in colorectal cancer and may serve as a prognostic tumor marker. Furthermore, these results provide a rationale for combining MET inhibitors with IFNs in preclinical trials. &lt;i&gt;Clin Cancer Res; 21(7); 1752–63. ©2015 AACR&lt;/i&gt;.&lt;/p&gt;&lt;/div&gt;