TPO-Induced Metabolic Reprogramming Drives Liver Metastasis of Colorectal Cancer CD110+ Tumor-Initiating Cells

Abstract Background: Metastasis and metabolic deregulation are two of the major hallmarks of cancer. Recent studies have revealed the critical driving role of metabolic reprogramming of tumor cells to promote colorectal cancer (CRC) metastasis. However, little is known about the metabolic alterations of cancer-associated fibroblasts (CAFs) in the pre-metastatic niche and how these changes facilitate CRC metastasis.Methods: Liquid chromatography-mass spectrometry (LC-MS) and Isobaric Tags for Relative and Absolute Quantitation (i-TRAQ) method were performed to identify the comparative metabolites and proteins expression in CAFs treated with exosomes derived from CRC cells, respectively. Tissue Microarray (TMA) was used to evaluate the level of HSPC111 in patient’s primary CRC tissues with or without liver metastasis. Co-immunoprecipitation (Co-IP), RNA-seq, chromatin immunoprecipitation (ChIP) migration and wound healing assay and immunofluorescence staining were employed to explore the expression regulation mechanism of exosomal HSPC111 in CAFs. Xenograft models were used to determine whether exosomal HSPC111 can remolding pre-metastatic niche of CAFs to promote CRC liver metastasis (CRLM) in vivo.Results: Here, we demonstrate that CRC cell-secreted exosomal HSPC111 induces a lipid metabolism reprogramming process in CAFs. Importantly, our results indicate that CRC patients with liver metastasis had significantly high level of HSPC111 in CRC tissues than CRC patients without liver metastasis. Mechanistically, HSPC111 upregulate the level of acetyl-CoA and histone acetylation by phosphorylating of ATP-citrate lyase (ACLY) in CAFs. This lipid metabolism reprogramming in CAFs facilitates CXCL5 secretion in vitro and pre-metastatic niche formation in the liver to promote CRLM in an exosomal HSPC111-dependent manner in vivo. In addition, conditioned medium (CM) from CAFs induce EMT of CRC cells by down-regulating E-cadherin levels and up-regulating Vimentin and Snail levels, which could be abolished by CXCL5-neutralizing antibody and CXCR2 inhibitor navarixin. Moreover, the HSPC111-ACLY association in CAFs was reinforced by CXCL5-CXCR2 axis, further promoting exosomal HSPC111 secretion from CRC cells to form a feedforward regulatory loop.Conclusion: Our present study reveals a novel insight into the pro-metastatic role of lipid metabolism reprogramming in CAFs and suggests the CXCL5-CXCR2 axis may be a promising target for halting CRLM.

Download Full-text

Faculty Opinions recommendation of Differentiated human colorectal cancer cells protect tumor-initiating cells from irinotecan.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.12734956.14001055 ◽

2011 ◽

Author(s):

Piet Borst

Keyword(s):

Colorectal Cancer ◽

Cancer Cells ◽

Human Colorectal Cancer ◽

Tumor Initiating Cells ◽

Colorectal Cancer Cells ◽

Human Colorectal Cancer Cells

Download Full-text

Cancer Stem Cell Niche in Colorectal Cancer and Targeted Therapies

Current Pharmaceutical Design ◽

10.2174/1381612826666200408102305 ◽

2020 ◽

Vol 26 (17) ◽

pp. 1979-1993 ◽

Cited By ~ 1

Author(s):

Hao Wang ◽

Guihua Cui ◽

Bo Yu ◽

Meiyan Sun ◽

Hong Yang

Keyword(s):

Colorectal Cancer ◽

Stem Cell Niche ◽

Tumor Initiating Cells ◽

Ideal Model ◽

Cytotoxic Effects ◽

Therapeutic Value ◽

Cancer Initiation ◽

Cell Niche ◽

New Strategies ◽

Common Malignancy

Cancer stem cells (CSCs), also known as tumor-initiating cells, are a sub-population of tumor cells found in many human cancers that are endowed with self-renewal and pluripotency. CSCs may be more resistant to conventional anticancer therapies than average cancer cells, as they can easily escape the cytotoxic effects of standard chemotherapy, thereby resulting in tumor relapse. Despite significant progress in related research, effective elimination of CSCs remains an unmet clinical need. CSCs are localized in a specialized microenvironment termed the niche, which plays a pivotal role in cancer multidrug resistance. The niche components of CSCs, such as the extracellular matrix, also physically shelter CSCs from therapeutic agents. Colorectal cancer is the most common malignancy worldwide and presents a relatively transparent process of cancer initiation and development, making it an ideal model for CSC niche research. Here, we review recent advances in the field of CSCs using colorectal cancer as an example to illustrate the potential therapeutic value of targeting the CSC niche. These findings not only provide a novel theoretical basis for in-depth discussions on tumor occurrence, development, and prognosis evaluation, but also offer new strategies for the targeted treatment of cancer.

Download Full-text

The prognostic role of KRAS and BRAF in patients undergoing surgical resection of colorectal cancer liver metastasis: a systematic review and meta-analysis

Annals of Oncology ◽

10.1093/annonc/mdw335.08 ◽

2016 ◽

Vol 27 ◽

pp. iv41

Author(s):

F. Passiglia ◽

A. Galvano ◽

S. Rizzo ◽

A. Listì ◽

N. Barraco ◽

...

Keyword(s):

Colorectal Cancer ◽

Systematic Review ◽

Liver Metastasis ◽

Surgical Resection ◽

Meta Analysis ◽

Prognostic Role ◽

Colorectal Cancer Liver Metastasis

Download Full-text

Stem cell gene Girdin: a potential early liver metastasis predictor of colorectal cancer

Molecular Biology Reports ◽

10.1007/s11033-012-1731-8 ◽

2012 ◽

Vol 39 (9) ◽

pp. 8717-8722 ◽

Cited By ~ 13

Author(s):

Chen Liu ◽

Hongpeng Xue ◽

Yixia Lu ◽

Baorong Chi

Keyword(s):

Colorectal Cancer ◽

Stem Cell ◽

Liver Metastasis ◽

Cell Gene ◽

Stem Cell Gene

Download Full-text

Liver Immune Microenvironment and Metastasis from Colorectal Cancer-Pathogenesis and Therapeutic Perspectives

Cancers ◽

10.3390/cancers13102418 ◽

2021 ◽

Vol 13 (10) ◽

pp. 2418

Author(s):

Xuezhen Zeng ◽

Simon E. Ward ◽

Jingying Zhou ◽

Alfred S. L. Cheng

Keyword(s):

Colorectal Cancer ◽

Liver Metastasis ◽

Cancer Patients ◽

High Recurrence Rate ◽

Immune Microenvironment ◽

Liver Sinusoidal Endothelial Cells ◽

Premetastatic Niche ◽

Cancer Pathogenesis ◽

Colorectal Cancer Patients ◽

The Impact

A drastic difference exists between the 5-year survival rates of colorectal cancer patients with localized cancer and distal organ metastasis. The liver is the most favorable organ for cancer metastases from the colorectum. Beyond the liver-colon anatomic relationship, emerging evidence highlights the impact of liver immune microenvironment on colorectal liver metastasis. Prior to cancer cell dissemination, hepatocytes secrete multiple factors to recruit or activate immune cells and stromal cells in the liver to form a favorable premetastatic niche. The liver-resident cells including Kupffer cells, hepatic stellate cells, and liver-sinusoidal endothelial cells are co-opted by the recruited cells, such as myeloid-derived suppressor cells and tumor-associated macrophages, to establish an immunosuppressive liver microenvironment suitable for tumor cell colonization and outgrowth. Current treatments including radical surgery, systemic therapy, and localized therapy have only achieved good clinical outcomes in a minority of colorectal cancer patients with liver metastasis, which is further hampered by high recurrence rate. Better understanding of the mechanisms governing the metastasis-prone liver immune microenvironment should open new immuno-oncology avenues for liver metastasis intervention.

Download Full-text

LncRNA MIR17HG promotes colorectal cancer liver metastasis by mediating a glycolysis-associated positive feedback circuit

Oncogene ◽

10.1038/s41388-021-01859-6 ◽

2021 ◽

Author(s):

Senlin Zhao ◽

Bingjie Guan ◽

Yushuai Mi ◽

Debing Shi ◽

Ping Wei ◽

...

Keyword(s):

Colorectal Cancer ◽

Liver Metastasis ◽

Positive Feedback ◽

Feedback Loop ◽

Metastatic Tumor ◽

Feedback Circuit ◽

Colorectal Cancer Liver Metastasis ◽

Positive Feedback Circuit

AbstractGlycolysis plays a crucial role in reprogramming the metastatic tumor microenvironment. A series of lncRNAs have been identified to function as oncogenic molecules by regulating glycolysis. However, the roles of glycolysis-related lncRNAs in regulating colorectal cancer liver metastasis (CRLM) remain poorly understood. In the present study, the expression of the glycolysis-related lncRNA MIR17HG gradually increased from adjacent normal to CRC to the paired liver metastatic tissues, and high MIR17HG expression predicted poor survival, especially in patients with liver metastasis. Functionally, MIR17HG promoted glycolysis in CRC cells and enhanced their invasion and liver metastasis in vitro and in vivo. Mechanistically, MIR17HG functioned as a ceRNA to regulate HK1 expression by sponging miR-138-5p, resulting in glycolysis in CRC cells and leading to their invasion and liver metastasis. More interestingly, lactate accumulated via glycolysis activated the p38/Elk-1 signaling pathway to promote the transcriptional expression of MIR17HG in CRC cells, forming a positive feedback loop, which eventually resulted in persistent glycolysis and the invasion and liver metastasis of CRC cells. In conclusion, the present study indicates that the lactate-responsive lncRNA MIR17HG, acting as a ceRNA, promotes CRLM through a glycolysis-mediated positive feedback circuit and might be a novel biomarker and therapeutic target for CRLM.

Download Full-text