• Colorectal neoplasms
• Doxorubicin
• Panobinostat
• Proto-Oncogene Proteins c-akt/glycogen synthase kinase-3 beta/mammalian target of rapamycin
• Sterol regulatory element binding protein 1

• Jeonbuk National University

• 5‐Fu
• JAK–STAT signalling pathway
• TIMP‐2
• colorectal cancer
• drug resistance

• Humans
• Fluorouracil/pharmacology
• Tissue Inhibitor of Metalloproteinase-2/metabolism
• Tissue Inhibitor of Metalloproteinase-2/genetics
• Tissue Inhibitor of Metalloproteinase-2/blood
• Colorectal Neoplasms/drug therapy
• Colorectal Neoplasms/metabolism
• Colorectal Neoplasms/pathology
• Colorectal Neoplasms/genetics
• Drug Resistance, Neoplasm/genetics
• Drug Resistance, Neoplasm/drug effects
• Signal Transduction/drug effects
• Cell Line, Tumor
• Janus Kinases/metabolism
• Cell Proliferation/drug effects
• Gene Expression Regulation, Neoplastic/drug effects
• STAT Transcription Factors/metabolism
• Male

• 2024 SKY040 Shaoxing Health Science and Technology Plan
• 2022SY014 Shaoxing Bureau of Science and Technology
• 2023A14006 Shaoxing Bureau of Science and Technology
• 2023KY1234 Medical Science and Technology Project of Zhejiang Province
• 2023KY1250 Medical Science and Technology Project of Zhejiang Province
• Shaoxing Bureau of Science and Technology
• Medical Science and Technology Project of Zhejiang Province

• Apostichopus japonicus
• EGFR
• HCT116 cells
• histidine-rich peptide
• rAj-HRP

• Humans
• Animals
• HCT116 Cells
• Colonic Neoplasms/drug therapy
• Colonic Neoplasms/pathology
• Colonic Neoplasms/metabolism
• Cell Proliferation/drug effects
• Apoptosis/drug effects
• Mice
• Cell Movement/drug effects
• Stichopus/chemistry
• Xenograft Model Antitumor Assays
• Mice, Inbred BALB C
• Peptides/pharmacology
• Peptides/chemistry
• Proteins/chemistry
• Proteins/pharmacology
• Proteins/genetics
• Antineoplastic Agents/pharmacology
• Antineoplastic Agents/chemistry
• Cell Adhesion/drug effects
• Signal Transduction/drug effects

• 2018YFD0900105 National Science and Technology Council

• Colorectal cancer
• EMT
• Metastasis
• PI3K/AKT
• Prognosis

• Humans
• Proto-Oncogene Proteins c-akt/metabolism
• Phosphatidylinositol 3-Kinases/metabolism
• Epithelial-Mesenchymal Transition
• Signal Transduction
• Cell Line, Tumor
• Cell Proliferation
• Cell Movement
• Colorectal Neoplasms/pathology
• Gene Expression Regulation, Neoplastic

• PLAGL2
• Serous ovarian cancer
• TEAD4

• No. RC190500 Shenyang Young and Middle-aged Innovation Support Project
• No. 2020-MS-063 Natural Science Foundation of Liaoning Province

Colorectal cancer (CRC) is the most common digestive malignancy across the world. Its first-line treatments applied in the routine clinical setting include surgery, chemotherapy, radiotherapy, targeted therapy, and immunotherapy. However, resistance to therapy has been identified as the major clinical challenge that fails the treatment method, leading to recurrence and distant metastasis. An increasing number of studies have been attempting to explore the underlying mechanisms of the resistance of CRC cells to different therapies, which can be summarized into two aspects: (1) The intrinsic characters and adapted alterations of CRC cells before and during treatment that regulate the drug metabolism, drug transport, drug target, and the activation of signaling pathways; and (2) the suppressive features of the tumor microenvironment (TME). To combat the issue of therapeutic resistance, effective strategies are warranted with a focus on the restoration of CRC cells’ sensitivity to specific treatments as well as reprogramming impressive TME into stimulatory conditions. To date, nanotechnology seems promising with scope for improvement of drug mobility, treatment efficacy, and reduction of systemic toxicity. The instinctive advantages offered by nanomaterials enable the diversity of loading cargoes to increase drug concentration and targeting specificity, as well as offer a platform for trying the combination of different treatments to eventually prevent tumor recurrence, metastasis, and reversion of therapy resistance. The present review intends to summarize the known mechanisms of CRC resistance to chemotherapy, radiotherapy, immunotherapy, and targeted therapy, as well as the process of metastasis. We have also emphasized the recent application of nanomaterials in combating therapeutic resistance and preventing metastasis either by combining with other treatment approaches or alone. In summary, nanomedicine is an emerging technology with potential for CRC treatment; hence, efforts should be devoted to targeting cancer cells for the restoration of therapeutic sensitivity as well as reprogramming the TME. It is believed that the combined strategy will be beneficial to achieve synergistic outcomes contributing to control and management of CRC in the future.

• Colorectal cancer
• Therapeutic resistance
• Nanotechnology
• Drug delivery system
• Combined treatment

• Humans
• Drug Resistance, Neoplasm
• Nanotechnology
• Drug Delivery Systems
• Immunotherapy
• Colorectal Neoplasms/drug therapy
• Tumor Microenvironment

Tumor-initiating cells (TICs) are a rare sub-population of cells within the bulk of a tumor that are major contributors to tumor initiation, metastasis, and chemoresistance. TICs have a stem-cell-like phenotype that is dictated by the expression of master regulator transcription factors, including OCT4, NANOG, and SOX2. These transcription factors are expressed via activation of multiple signaling pathways that drive cancer initiation and progression. Importantly, these same signaling pathways can be activated by select chemokine receptors. Chemokine receptors are increasingly being revealed as major drivers of the TIC phenotype, as their signaling can lead to activation of stemness-controlling transcription factors. Additionally, the cell surface expression of chemokine receptors provides a unique therapeutic target to disrupt signaling pathways that control the expression of master regulator transcription factors and the TIC phenotype. This review summarizes the master regulator transcription factors known to dictate the TIC phenotype, along with the complex signaling pathways that can mediate their expression and the chemokine receptors that are most upstream of this phenotype.

• Chemokines
• Initiation
• Metastasis
• Pluripotency

Plenty of factors affect the oncogenesis and progression of colorectal cancer in the tumor microenvironment, including various immune cells, stromal cells, cytokines, and other factors. Chemokine is a member of the cytokine superfamily. It is an indispensable component in the tumor microenvironment. Chemokines play an antitumor or pro-tumor role by recruitment or polarization of recruiting immune cells. Meanwhile, chemokines, as signal molecules, participate in the formation of a cross talk among signaling pathways and non-coding RNAs, which may be involved in promoting tumor progression. In addition, they also function in immune escape. Chemokines are related to drug resistance of tumor cells and may even provide reference for the diagnosis, therapy, and prognosis of patients with colorectal cancer.

• Chemokines/metabolism
• Colorectal Neoplasms/diagnosis
• Colorectal Neoplasms/drug therapy
• Colorectal Neoplasms/metabolism
• Cytokines/metabolism
• Drug Resistance, Neoplasm
• Humans
• Prognosis
• Tumor Microenvironment

• PD-L1, immune evasion
• cancer-associated fibroblasts (CAFs)
• colorectal cancer (CRC)
• immune cell infiltration
• integrin-linked kinase (ILK)
• tumor microenvironment (TME)

Background: Heat shock protein B8 (HSPB8) is expressed in various cancers. However, the functional and clinicopathological significance of HSPB8 expression in bladder cancer (BC) remains unclear. The present study sought to elucidate the clinicopathological features and prognostic value of HSPB8 in BC.

Methods: A BC RNA-seq data set was obtained from The Cancer Genome Atlas Urothelial Bladder Carcinoma (TCGA-BLCA) database, and the external validation dataset GSE130598 was downloaded from the GEO database. Samples in the TCGA-BLCA were categorized into two groups based on HSPB8 expression. Differentially expressed genes (DEGs) between the two groups were defined as HSPB8 co-expressed genes. Gene set enrichment analysis (GSEA), protein-protein interaction networks, and mRNA-microRNA (miRNA) interaction networks were generated to predict the function and interactions of genes that are co-expressed with HSPB8. Finally, we examined immune cell infiltration and constructed a survival prediction model for BC patients.

Results: The expression level of HSBP8 has a significant difference between cancer samples and normal samples, and its diagnosis effect was validated by the ROC curve. 446 differential expressed genes between HSBP8 high-expression and HSBP8 low expression groups were identified. Gene enrichment analysis and GSEA analysis show that these differential gene functions are closely related to the occurrence and development of BC and the metabolic pathways of BC. The cancer-related pathways included Cytokine-cytokine receptor Interaction, Focal adhesion, and Proteoglycans in cancer. PPI and protein-coding gene-miRNA network visualized the landscape for these tightly bounded gene interactions. Immune cell infiltration shows that B cells, CD4+T cells, and CD8+T cells have strongly different infiltration levels between the HSBP8 high exp group and low exp group. The survival prediction model shows that HSBP8 has strong prognosis power in the BLCA cohort.

Conclusion: Identifying DEGs may enhance understanding of BC development’s causes and molecular mechanisms. HSPB8 may play an essential role in BC progression and prognosis and serve as a potential biomarker for BC treatment.

• HSPB8
• biomarker
• bladder cancer
• microarray
• prognosis

• AKT/GSK-3β/Snail signaling
• COL11A1
• EMT and cell stemness
• migration and invasion
• pancreatic cancer

• Cell Line, Tumor
• Cell Movement
• Collagen Type XI/metabolism
• Epithelial-Mesenchymal Transition
• Glycogen Synthase Kinase 3 beta/genetics
• Humans
• Pancreatic Neoplasms/genetics
• Proto-Oncogene Proteins c-akt/metabolism
• Snail Family Transcription Factors/genetics
• Snail Family Transcription Factors/metabolism
• Pancreatic Neoplasms

There are promising new therapeutic agents for CRC patients, including novel small-molecule inhibitors and immune checkpoint blockers. We focused on emerging CRC’s therapeutic agents that have shown the potential for progress in clinical practice. This review provides an overview of tyrosine kinase inhibitors targeting VEGF and KIT, BRAF and MEK inhibitors, TLR9 agonist, STAT3 inhibitors, and immune checkpoint blockers (PD1/PDL-1 inhibitors), for which recent advances have been reported. These new agents have the potential to provide benefits to CRC patients with unmet medical needs.

Resistance against conventional chemotherapeutic agents is one of the main reasons for tumor relapse and poor clinical outcomes in cancer patients. Various mechanisms are associated with drug resistance, including drug efflux, cell cycle, DNA repair and apoptosis. Doxorubicin (DOX) is a widely used first-line anti-cancer drug that functions as a DNA topoisomerase II inhibitor. However, DOX resistance has emerged as a large hurdle in efficient tumor therapy. Furthermore, despite its wide clinical application, DOX is a double-edged sword: it can damage normal tissues and affect the quality of patients’ lives during and after treatment. It is essential to clarify the molecular basis of DOX resistance to support the development of novel therapeutic modalities with fewer and/or lower-impact side effects in cancer patients. Long non-coding RNAs (lncRNAs) have critical roles in the drug resistance of various tumors. In this review, we summarize the state of knowledge on all the lncRNAs associated with DOX resistance. The majority are involved in promoting DOX resistance. This review paves the way to introducing an lncRNA panel marker for the prediction of the DOX response and clinical outcomes for cancer patients.

• Cancer
• Chemotherapy
• Doxorubicin
• Drug resistance

Programmed death‐ligand 1 (PD‐L1) blockade has revolutionized the prognosis of several cancers, but shows a weak effect on pancreatic cancer (PC) due to poor effective immune infiltration. Chemokine C‐C motif ligand 21 (CCL21), a chemokine promoting T cell immunity by recruiting and colocalizing dendritic cells (DCs) and T cells, serves as a potential antitumor agent in many cancers. However, its antitumor response and mechanism combined with PD‐L1 blockade in PC remain unclear. In our study, we found CCL21 played an important role in leukocyte chemotaxis, inflammatory response, and positive regulation of PI3K‐AKT signaling in PC using Metascape and gene set enrichment analysis. The CCL21 level was verified to be positively correlated with infiltration of CD8⁺ T cells by the CIBERSORT algorithm, but no significant difference in survival was observed in either The Cancer Genome Atlas or the International Cancer Genome Consortium cohort when stratified by CCL21 expression. Additionally, we found the growth rate of allograft tumors was reduced and T cell infiltration was increased, but tumor PD‐L1 abundance elevated simultaneously in the CCL21‐overexpressed tumors. Then, CCL21 was further verified to increase tumor PD‐L1 level through the AKT‐glycogen synthase kinase‐3β axis in human PC cells, which partly impaired the antitumor T cell immunity. Finally, the combination of CCL21 and PD‐L1 blockade showed superior synergistic tumor suppression in vitro and in vivo. Together, our findings suggested that CCL21 in combination with PD‐L1 blockade might be an efficient and promising option for the treatment of PC.

• CCL21
• PD-L1
• T cell infiltration
• combination therapy
• pancreatic cancer

• Ischemia–reperfusion
• Nervous system
• Resveratrol

• Cancer Stem Cells
• Colorectal Cancer
• Intra-Tumor Heterogeneity
• Omic Technologies
• Single-Cell Analyses
• Targeted Therapies

• CCL19
• CCL21
• CCR7
• Cancer
• Chemokine
• Immunotherapy
• Metastasis
• Therapy

AKT, a serine threonine kinase, exists in three different isoforms and is known for regulating several biological processes including tumorigenesis. In this study, we investigated the expression and net effect of the individual isoforms in triple negative breast cancers and response to cisplatin treatment using cellular, mice models and clinical samples. Interestingly, analysis of the expressions of AKT isoforms in clinical samples showed relatively higher expression of AKT1 in primary tissues; whereas lung and liver metastatic samples showed elevated expression of AKT2. Similarly, triple-negative breast cancer cell lines, BT-549 and MDA-MB-231, with high proliferative and invasive properties, displayed higher expression levels of AKT1/2. By modulating AKT isoform expression in MCF-10A and BT-549 cell lines, we found that presence of AKT2 was associated with invasiveness, stemness and sensitivity to drug treatment. It was observed that the silencing of AKT2 suppressed the cancer stem cell populations (CD44^high CD24^low, ALDH1), mammosphere formation, invasive and migratory potential in MCF-10A and BT-549 cells. It was further demonstrated that loss of function of AKT1 isoform is associated with reduced sensitivity towards cisplatin treatment in triple-negative breast cancers cellular and syngeneic mice models. The decrease in cisplatin treatment response in shAKT1 cells was allied with the upregulation in the expression of transporter protein ABCG2, whereas silencing of ABCG2 restored cisplatin sensitivity in these cells through AKT/SNAIL/ABCG2 axis. In conclusion, our study demonstrated the varied expression of AKT isoforms in triple-negative breast cancers and also confirmed differential role of isoforms in stemness, invasiveness and response towards the cisplatin treatment.

• ABCG2
• AKT isoform
• CSCs
• TNBCs
• drug resistance

• 5-fluorouracil
• colorectal cancer
• resistance mechanism

• BI9564
• Bromodomain-containing protein 9 (BRD9)
• MGC-803 cells
• calcium voltage-gated channel auxiliary subunit alpha2 delta 4 (CANA2D4)
• calmodulin-like 6 (CALML6)
• combination therapy

Long non-coding RNAs (lncRNAs) are recognized as critical regulators of self-renewal in human cancer stem-like cells (CSCs), which are a subpopulation of cancer cells primarily responsible for the malignant features of cancer. However, most CSC-related lncRNAs remain unidentified. The results of the present study suggested that growth-arrest-specific transcript 5 (GAS5), a tumor suppressor, exhibited increased expression and was associated with malignant features in human colorectal cancer cell HCT116-derived CSCs. Phenotypic analysis indicated that GAS5 knockdown by specific siRNA significantly decreased CSC self-renewal capacity, proliferation and migration. Moreover, GAS5 knockdown sensitized CSCs to the chemotherapeutic agents 5-fluorouracil and doxorubicin by inducing apoptosis detected by Annexin V-FITC/PI double staining. Inhibition of Nodal growth differentiation factor (NODAL) signaling, which has been reported to be protected by GAS5, presented similar chemosensitivity effects to the GAS5 knockdown results. The present study also assessed the effects of GAS5 overexpression on HCT116 cells, and revealed that overexpression of GAS5 sensitized HCT116 cells to chemotherapeutic agents, which is the opposite of the effect observed in CSCs derived from HCT116 cells. Therefore, it was hypothesized that GAS5 may function as a critical factor for maintaining stemness and that it may exert protective effects on CSCs in a NODAL-dependent manner. Collectively, the results of the present study indicate that GAS5 may be a promising therapeutic target for overcoming malignant features and chemoresistance in colorectal cancer cells.

• Nodal growth differentiation factor
• cancer stem-like cells
• chemoresistance
• growth-arrest-specific transcript 5
• long non-coding RNA

• ABC transporter druggability
• ABC transporters
• Cancer initiation
• Cancer progression
• Cancer stem cells
• Epithelial mesenchymal transition

• ATP-Binding Cassette Transporters/chemistry
• ATP-Binding Cassette Transporters/genetics
• ATP-Binding Cassette Transporters/metabolism
• Animals
• Biomarkers
• Cell Transformation, Neoplastic/genetics
• Cell Transformation, Neoplastic/metabolism
• Disease Progression
• Disease Susceptibility
• Drug Resistance, Neoplasm/genetics
• Epithelial-Mesenchymal Transition/genetics
• Gene Expression Regulation, Neoplastic
• Humans
• Neoplasms/drug therapy
• Neoplasms/etiology
• Neoplasms/metabolism
• Neoplasms/pathology
• Neoplastic Stem Cells/metabolism
• Signal Transduction
• Structure-Activity Relationship

• Follicular variant papillary thyroid carcinoma (FVPTC)
• bioinformatics
• hub gene
• protein-protein interaction network (PPI network)
• receiver operating characteristic (ROC)

The identification of safe and effective drugs that inhibit tumor invasion and metastasis is required to improve the clinical outcome of patients with colon cancer. The present study aimed to investigate the inhibitory effects and possible mechanisms of action of resveratrol against the invasion and metastasis of colon cancer. AKT1-knockdown SW480 and SW620 colon cancer cells were used to detect the effects of resveratrol on cell invasion and metastasis, as well as changes in the expression of epithelial-mesenchymal transition (EMT) markers and serine/threonine kinase (AKT)/glycogen synthase kinase (GSK)-3β/Snail signaling pathway-related molecules in vitro. Furthermore, nude mice were inoculated with SW480 cells in the tail vein to establish an in vivo lung metastasis model of colon cancer, to investigate the effects of resveratrol on lung metastasis in colon cancer. The results revealed that resveratrol treatment and AKT1 knockdown significantly inhibited cell migration and invasion in colon cancer, and markedly increased E-cadherin expression and decreased that of N-cadherin, phospho (p)-AKT1, p-GSK-3β, and Snail in colon cancer both in vitro and in vivo. Furthermore, the effects of resveratrol were significantly weaker in the AKT1-knockdown cells. In conclusion, resveratrol may suppress the invasion and metastasis of colon cancer through reversal of EMT via the AKT/GSK-3β/Snail signaling pathway. AKT1 may therefore be a key regulator of EMT in colon cancer cells and a potential therapeutic target for this disease.

Long non-coding RNAs (lncRNAs) play critical roles in the development and progression of cancers. The present study aimed to identify novel lncRNAs and associated microRNAs (miRNAs or miRs) and mRNAs in gastric cancer. Differentially expressed lncRNAs (DElncRNAs) and differentially expressed mRNAs (DEmRNAs) of 6 paired gastric cancer and normal tissues were identified using microarray. The DEmiRNAs between gastric cancer and the normal control tissues were identified using miRNA-seq data from Cancer Genome Atlas. Common DElncRNAs from the Cancer RNA-Seq Nexus database and circlncRNAnet database were analyzed. A DElncRNAs-DEmiRNAs-DEmRNAs network was constructed by target prediction. Functional enrichment analysis was employed to predict the function of DEmRNAs in the network. The correlation between the expression of DElncRNAS and DEmRNAs in the network was analyzed. The expression levels of several genes were validated by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). A total of 1,297 DElncRNAs, 2,037 DEmRNAs and 171 DEmiRNAs were identified. Among the 4 lncRNAs common to the 3 datasets, prostate androgen-regulated transcript 1 (PART1) was selected for further analysis. The analysis identified 5 DEmiRNAs and 13 DEmRNAs in the PART1-mediated ceRNA network. The DEmRNAs in the ceRNA network were markedly enriched in cancer-related biological processes (response to hypoxia, positive regulation of angiogenesis and positive regulation of endothelial cell proliferation) and pathways (cGMP-PKG signaling pathway, cAMP signaling pathway and proteoglycans in cancer). Out of the 13 DEmRNAs, 11 were positively associated with PART1. The downregulation of PART1, myosin light chain 9 (MYL9), potassium calcium-activated channel subfamily M alpha 1 (KCNMA1), cholinergic receptor muscarinic 1 (CHRM1), solute carrier family 25 member 4 (SLC25A4) and ATPase Na⁺/K⁺ transporting subunit alpha 2 (ATP1A2) expression levels in gastric cancer was validated by RT-qPCR. On the whole, the current study identified a novel lncRNA and associated miRNAs and mRNAs that are involved in the pathogenesis of gastric cancer that may serve as potential therapeutic targets for the treatment of gastric cancer.

• ATM
• Akt/GSK-3β/snail
• Ovarian cancer
• miR-203a-3p

• Akt
• Stat3
• acetyl-11-keto-β-boswellic acid
• chemoresistant stem cell-like properties
• docetaxel-resistance
• prostate cancer

• biomarkers
• chemokines
• diffuse large B-cell lymphoma

• P-glycoprotein
• bimodal change
• brain distribution
• epithelial-to-mesenchymal transition
• ezrin, radixin and moesin (ERM) protein
• membrane localization

肺癌发病率逐年上升，有必要寻找新型的治疗靶点，而最新研究发现囊状纤维化跨膜转导调节子（cystic fibrosis transmembrane conductance regulator, CFTR）与多种肿瘤的发生和恶性转化有关。本研究探讨CFTR对肺癌A549细胞恶性特性的影响。

应用CCK8细胞增殖实验、细胞划痕实验、Transwell细胞侵袭实验以及克隆形成实验等方法分别检测CFTR的表达对非小细胞肺癌A549细胞的增殖、迁移、侵袭等细胞恶性特性的影响。同时通过免疫印迹（Western blot）分析CFTR基因表达对肿瘤干细胞相关转录因子表达的影响。

过表达CFTR基因显著抑制A549细胞的增殖、迁移、侵袭和克隆形成等肿瘤恶性特征，而RNA干扰A549细胞CFTR的表达导致细胞上述特征的明显增强。免疫印迹实验进一步发现CFTR基因过表达抑制A549细胞中干细胞相关转录因子SOX2和OCT3/4，以及细胞表面CD133蛋白的表达；相反，RNA干扰A549细胞中CFTR基因的表达增加SOX2、OCT4和CD133的表达。然而，免疫印迹和流式细胞术发现CFTR基因表达对A549细胞肺癌干细胞标志乙醛脱氢酶1的表达和阳性细胞数量无显著影响。

CFTR基因在肺癌A549细胞中具有抑制细胞恶性特征的作用，提示其可能是肺腺癌治疗的一个新的靶点，但其对其他肺腺癌细胞的作用与分子机制还有待进一步研究。

• A549 cells
• Cystic fibrosis transmembrane conductance regulators
• Lung neoplasms

• Tumor microenvironment (TME)
• cancer stem cells (CSCs)
• chemoresistance
• drug delivery approaches
• immune infiltrates

The underlying cause of treatment failure in many cancer patients is intrinsic and acquired resistance to chemotherapy. Recently, histone deacetylase (HDAC) inhibitors have developed into a promising cancer treatment. However, resistance mechanism induced by HDAC inhibitors remains largely unknown. Here we report that a HDAC inhibitor, JNJ-2648158 induced transcription of XIAP by activating AP-1 expression, which conferring resistance to chemotherapeutics. Our results showed that high expression of c-Fos caused by HDAC inhibitor promoted AP-1 formation during acquired resistance towards chemo-drugs, indicating an extremely poor clinical outcome in breast cancers and liver cancers. Our study reveals a novel regulatory mechanism towards chemo-drug resistance, and suggests that XIAP may serve as a potential therapeutic target in those chemo-resistant cancer cells.

• AP-1
• HDAC inhibitor
• JNJ26481585
• XIAP
• drug resistant

Colorectal cancer is one of the most common cancers worldwide with high mortality. Distant metastasis and relapse are major causes of patient death. Cancer stem cells (CSCs) play a critical role in the metastasis and relapse of colorectal cancer. CSCs are a subpopulation of cancer cells with unique properties of self-renewal, infinite division and multi-directional differentiation potential. Colorectal CSCs are defined with a group of cell surface markers, such as CD44, CD133, CD24, EpCAM, LGR5 and ALDH. They are highly tumorigenic, chemoresistant and radioresistant and thus are critical in the metastasis and recurrence of colorectal cancer and disease-free survival. This review article updates the colorectal CSCs with a focus on their role in tumor initiation, progression, drug resistance and tumor relapse.

• cancer stem cells
• colorectal cancer
• epithelial mesenchymal transition
• metastasis
• tumor microenvironment

Cancer-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.

Snail-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.

Snail-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.

Taken 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.

• CCL1
• Cancer-associated fibroblasts
• Multidrug resistance
• Snail
• Colorectal neoplasms