scholarly journals Hepatic Thermal Injury Promotes Colorectal Cancer Engraftment in C57/black 6 Mice

2020 ◽  
Author(s):  
Alison L. Halpern ◽  
J. Gregory Fitz ◽  
Yuki Fujiwara ◽  
Jeniann Yi ◽  
Aimee L. Anderson ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Thermal Ablation ◽  
Thermal Injury ◽  
Tumor Development ◽  
Hepatic Metastases ◽  
Local Environment ◽  
Surgical Approaches ◽  
Recurrence Rates ◽  
Poor Outcomes ◽  
Argon Beam Coagulation

Background:Treatment of liver metastases (primarily colorectal cancer) is limited by high recurrence rates and tumor progression. Surgical approaches to management of these metastases typically utilize heat energy: including electrocautery; argon beam coagulation; thermal ablation of surgical margins for hemostasis; and preemptive thermal ablation to prevent bleeding or effect tumor destruction. Based on high rates of local recurrence, these studies assess whether local effects of hepatic thermal injury (HTI) might contribute to poor outcomes by promoting a hepatic microenvironment favorable for tumor engraftment or progression due to induction of pro-cancer cytokines and deleterious immune infiltrates at the site of thermal injury. Approach and Results:To test this hypothesis, an immunocompetent mouse model was developed wherein HTI was combined with concomitant intrasplenic injection of cells from a well characterized MC38 colon carcinoma cell line. In this model, HTI resulted in a significant increase in engraftment and progression of MC38 tumors at the site of thermal injury. Further, there were local increases in expression of mRNA for Hif1a, Arg1, and Vegfaand activation changes in recruited macrophages at the HTI site but not in untreated liver tissue. Inhibition of HIF1α following HTI significantly reduced discreet hepatic tumor development (p=0.03). Conclusions:Taken together, these findings demonstrate that HTI creates a favorable local environment that is associated with pro-tumorigenic activation of macrophages and circulating tumors implanting. Discrete targeting of HIF1α and/or its up and downstream pathways and/or inhibiting macrophages offer potential strategies for improving the outcome of surgical management of hepatic metastases where HTI is utilized.

scholarly journals A New Light on Potential Therapeutic Targets for Colorectal Cancer Treatment

Biomedicines ◽  
2021 ◽  
Vol 9 (10) ◽  
pp. 1438
Author(s):  
Wei-Lun Tsai ◽  
Chih-Yang Wang ◽  
Yu-Cheng Lee ◽  
Wan-Chun Tang ◽  
Gangga Anuraga ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Biology ◽  
Molecular Mechanisms ◽  
Tumor Development ◽  
Gene Expression Omnibus ◽  
Different Types ◽  
Geo Dataset ◽  
Non Coding Rnas ◽  
Poor Outcomes ◽  
Upregulated Genes

The development and progression of colorectal cancer (CRC) involve changes in genetic and epigenetic levels of oncogenes and/or tumor suppressors. In spite of advances in understanding of the molecular mechanisms involved in CRC, the overall survival rate of CRC still remains relatively low. Thus, more research is needed to discover and investigate effective biomarkers and targets for diagnosing and treating CRC. The roles of long non-coding RNAs (lncRNAs) participating in various aspects of cell biology have been investigated and potentially contribute to tumor development. Our recent study also showed that CRNDE was among the top 20 upregulated genes in CRC clinical tissues compared to normal colorectal tissues by analyzing a Gene Expression Omnibus (GEO) dataset (GSE21815). Although CRNDE is widely reported to be associated with different types of cancer, most studies of CRNDE were limited to examining regulation of its transcription levels, and in-depth mechanistic research is lacking. In the present study, CRNDE was found to be significantly upregulated in CRC patients at an advanced TNM stage, and its high expression was correlated with poor outcomes of CRC patients. In addition, we found that knocking down CRNDE could reduce lipid accumulation through the miR-29b-3p/ANGPTL4 axis and consequently induce autophagy of CRC cells.

Prognostic implications of TAMs in colorectal cancer hepatic metastases.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 3574-3574 ◽  
Author(s):  
Matthew Reilley ◽  
Sreyashi Basu ◽  
Riham Katkhuda ◽  
Nicolle Patterson ◽  
Tenghui Chen ◽  
...  
Keyword(s):  
Gene Expression ◽  
Colorectal Cancer ◽  
T Cell ◽  
Liver Metastases ◽  
Hepatic Metastases ◽  
Principal Component ◽  
Recurrence Risk ◽  
Recurrent Tumors ◽  
Poor Outcomes ◽  
Immune Related Genes

3574 Background: A limited understanding of the immune microenvironment of mismatch repair-proficient metastatic colorectal cancer (mCRC) impedes efforts to develop effective immunotherapy treatments for the majority of CRC patients. Liver metastatic disease is common and associated with poor outcomes. While T-cell infiltration of liver metastases positively correlates with survival, most mCRC patients do not benefit from checkpoint-blockade therapy. Tissue associated macrophages (TAMs) have been associated with an immune suppressive environment, but their prognostic role in mCRC is largely unknown. Methods: Comprehensive analysis of gene expression and immunohistochemistry (IHC) in 25 microsatellite stable (MSS) untreated liver metastatectomy (LM) specimens was performed. Clinical outcomes including recurrence, immunologic data, and tumor microsatellite status were evaluated and correlated. Results: Principal component analysis of immune and cancer pathway related genes were performed and compared with recurrence status. All samples were confirmed MSS. There were distinct differences in gene expression between patients who remained disease free and those who recurred. Among immune related genes CXCL5, IRF4, IL6R, TNF, CTLA4, ICOS, and ARG1 were relatively over-expressed in non-recurrent tumors, while PPARG, AIRE, and EPCAM were over-expressed in recurrent tumors (FDR 0.2, p < 0.05). Cibersort analysis predicts a significantly higher number of M2 versus M1 macrophages regardless of recurrence status (p < 0.05), with an approximate M1:M2 ratio of 1:2 and a higher total number of M1/M2 macrophages in tumors that recur. On IHC, an average of 29% of cells per sample expressed macrophage marker CD68. Relatively fewer CD3, CD4, and CD8 T cells were observed with average infiltration rates of 7.4%, 3.6%, and 2.6% respectively. Conclusions: CRC liver metastases demonstrate evidence of a large TAM population with significant M2 component and a smaller T cell population. A greater number of TAMs appear to correlate with recurrence, while a more immunogenic phenotype correlates with lower recurrence risk.

Changes in the CEA gene are a basis for the lack of hepatic metastases in a spontaneous colorectal cancer primate model

2001 ◽  
Vol 120 (5) ◽  
pp. A167-A167
Author(s):  
R ZIMMER ◽  
P THOMAS ◽  
N CLAPP ◽  
C STANNERS ◽  
M TOBI ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Hepatic Metastases ◽  
Primate Model ◽  
Cea Gene

scholarly journals LAT1 and ASCT2 Related microRNAs as Potential New Therapeutic Agents against Colorectal Cancer Progression

Biomedicines ◽  
2021 ◽  
Vol 9 (2) ◽  
pp. 195
Author(s):  
Francisca Dias ◽  
Cristina Almeida ◽  
Ana Luísa Teixeira ◽  
Mariana Morais ◽  
Rui Medeiros
Keyword(s):  
Colorectal Cancer ◽  
Amino Acid ◽  
Cancer Progression ◽  
Cell Metabolism ◽  
Tumor Development ◽  
Amino Acid Transporters ◽  
Epigenetic Alterations ◽  
Therapeutic Approaches ◽  
Colorectal Cancer Progression ◽  
Made In

The development and progression of colorectal cancer (CRC) have been associated with genetic and epigenetic alterations and more recently with changes in cell metabolism. Amino acid transporters are key players in tumor development, and it is described that tumor cells upregulate some AA transporters in order to support the increased amino acid (AA) intake to sustain the tumor additional needs for tumor growth and proliferation through the activation of several signaling pathways. LAT1 and ASCT2 are two AA transporters involved in the regulation of the mTOR pathway that has been reported as upregulated in CRC. Some attempts have been made in order to develop therapeutic approaches to target these AA transporters, however none have reached the clinical setting so far. MiRNA-based therapies have been gaining increasing attention from pharmaceutical companies and now several miRNA-based drugs are currently in clinical trials with promising results. In this review we combine a bioinformatic approach with a literature review in order to identify a miRNA profile with the potential to target both LAT1 and ASCT2 with potential to be used as a therapeutic approach against CRC.

scholarly journals Role of Thermal Ablation in Colorectal Cancer Lung Metastases

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 908
Author(s):  
Alexandre Delpla ◽  
Thierry de Baere ◽  
Eloi Varin ◽  
Frederic Deschamps ◽  
Charles Roux ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Prognostic Factors ◽  
Thermal Ablation ◽  
Medical Oncology ◽  
Pulmonary Metastases ◽  
Lung Metastases ◽  
Stereotactic Ablative Radiotherapy ◽  
Chest Drainage ◽  
Results Of Surgery

Background: Consensus guidelines of the European Society for Medical Oncology (ESMO) (2016) provided recommendations for the management of lung metastases. Thermal ablation appears as a tool in the management of these secondary pulmonary lesions, in the same manner as surgical resection or stereotactic ablative radiotherapy (SABR). Methods: Indications, technical considerations, oncological outcomes such as survival (OS) or local control (LC), prognostic factors and complications of thermal ablation in colorectal cancer lung metastases were reviewed and put into perspective with results of surgery and SABR. Results: LC rates varied from 62 to 91%, with size of the metastasis (<2 cm), proximity to the bronchi or vessels, and size of ablation margins (>5 mm) as predictive factors of LC. Median OS varied between 33 and 68 months. Pulmonary free disease interval <12 months, positive carcinoembryonic antigen, absence of neoadjuvant chemotherapy and uncontrolled extra-pulmonary metastases were poor prognostic factors for OS. While chest drainage for less than 48 h was required in 13 to 47% of treatments, major complications were rare. Conclusions: Thermal ablation of a selected subpopulation of patients with colorectal cancer lung metastases is safe and can provide excellent LC and delay systemic chemotherapy.

scholarly journals Interleukin-11-expressing fibroblasts have a unique gene signature correlated with poor prognosis of colorectal cancer

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Takashi Nishina ◽  
Yutaka Deguchi ◽  
Daisuke Ohshima ◽  
Wakami Takeda ◽  
Masato Ohtsuka ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Tumor Cells ◽  
Human Cancer ◽  
Tumor Development ◽  
Gene Signature ◽  
Free Survival ◽  
Expression Of Genes ◽  
Reporter Mice ◽  
Interleukin 11

AbstractInterleukin (IL)-11 is a member of the IL-6 family of cytokines and is involved in multiple cellular responses, including tumor development. However, the origin and functions of IL-11-producing (IL-11+) cells are not fully understood. To characterize IL-11+ cells in vivo, we generate Il11 reporter mice. IL-11+ cells appear in the colon in murine tumor and acute colitis models. Il11ra1 or Il11 deletion attenuates the development of colitis-associated colorectal cancer. IL-11+ cells express fibroblast markers and genes associated with cell proliferation and tissue repair. IL-11 induces the activation of colonic fibroblasts and epithelial cells through phosphorylation of STAT3. Human cancer database analysis reveals that the expression of genes enriched in IL-11+ fibroblasts is elevated in human colorectal cancer and correlated with reduced recurrence-free survival. IL-11+ fibroblasts activate both tumor cells and fibroblasts via secretion of IL-11, thereby constituting a feed-forward loop between tumor cells and fibroblasts in the tumor microenvironment.

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