Lactic acid promotes metastatic niche formation in bone metastasis of colorectal cancer

Qian, Jin; Gong, Zhaohui; Zhang, Yina; Wu, Hongyan; Zhao, Jing; Wang, Liting; Yang, Lijuan; Liu, Da; Wang, Wei; Kang, Xin; Sheng, Jun; Xu, Wei; Li, Xilin; Wu, Juan; Wei, Zheng

doi:10.1186/s12964-020-00667-x

Cited by 40 publications

(22 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It was reported that high active Warburg effect could be detected in colorectal cancer cells [24]. In our previous study, we found lactate could promote the production of CXCL10 in early OCPs to recruit CD4+ T cells [25]. Together with this study, these results indicated that lactate may broadly modulate the secreting spectrum of chemoattractant proteins to facilitate the formation of metastatic microenvironment.…”

Section: Discussionsupporting

confidence: 78%

CCL7 playing a dominant role in recruiting early OCPs to facilitate osteolysis at metastatic site of colorectal cancer

Yang

Qian³

et al. 2022

Cell Commun Signal

View full text Add to dashboard Cite

Background Chemoattractant is critical to recruitment of osteoclast precursors and stimulates tumor bone metastasis. However, the role of chemoattractant in bone metastasis of colorectal cancer (CRC) is still unclear. Methods Histochemistry analysis and TRAP staining were utilized to detect the bone resorption and activation of osteoclasts (OCs) after administration of CCL7 neutralizing antibody or CCR1 siRNA. qRT-PCR analysis and ELISA assay were performed to detect the mRNA level and protein level of chemoattractant. BrdU assay and Tunel assay were used to detect the proliferation and apoptosis of osteoclast precursors (OCPs). The migration of OCPs was detected by Transwell assay. Western blots assay was performed to examine the protein levels of pathways regulating the expression of CCL7 or CCR1. Results OCPs-derived CCL7 was significantly upregulated in bone marrow after bone metastasis of CRC. Blockage of CCL7 efficiently prevented bone resorption. Administration of CCL7 promoted the migration of OCPs. Lactate promoted the expression of CCL7 through JNK pathway. In addition, CCR1 was the most important receptor of CCL7. Conclusion Our study indicates the essential role of CCL7-CCR1 signaling for recruitment of OCPs in early bone metastasis of CRC. Targeting CCL7 or CCR1 could restore the bone volume, which could be a potential therapeutical target.

show abstract

Section: Discussionsupporting

confidence: 78%

CCL7 playing a dominant role in recruiting early OCPs to facilitate osteolysis at metastatic site of colorectal cancer

Yang

Qian³

et al. 2022

Cell Commun Signal

View full text Add to dashboard Cite

show abstract

“…Recent studies have revealed that lactate contributes to the development of bone metastasis by directly regulating osteoclastogenesis. Qian et al reported that lactic acid promoted a bone metastatic niche for colorectal cancer 38 . Osteoclasts incorporate lactate that is released from breast cancer cells through MCT1 and use this lactate as a fuel to increase oxidative metabolism, thereby promoting bone resorption 39 .…”

Section: Discussionmentioning

confidence: 99%

The lactate sensor GPR81 regulates glycolysis and tumor growth of breast cancer

Ishihara

Hata

Hirose

et al. 2022

Sci Rep

View full text Add to dashboard Cite

Metabolic reprogramming is a malignant phenotype of cancer. Cancer cells utilize glycolysis to fuel rapid proliferation even in the presence of oxygen, and elevated glycolysis is coupled to lactate fermentation in the cancer microenvironment. Although lactate has been recognized as a metabolic waste product, it has become evident that lactate functions as not only an energy source but a signaling molecule through the lactate receptor G-protein-coupled receptor 81 (GPR81) under physiological conditions. However, the pathological role of GPR81 in cancer remains unclear. Here, we show that GPR81 regulates the malignant phenotype of breast cancer cell by reprogramming energy metabolism. We found that GPR81 is highly expressed in breast cancer cell lines but not in normal breast epithelial cells. Knockdown of GPR81 decreased breast cancer cell proliferation, and tumor growth. Mechanistically, glycolysis and lactate-dependent ATP production were impaired in GPR81-silenced breast cancer cells. RNA sequencing accompanied by Gene Ontology enrichment analysis further demonstrated a significant decrease in genes associated with cell motility and silencing of GPR81 suppressed cell migration and invasion. Notably, histological examination showed strong expression of GPR81 in clinical samples of human breast cancer. Collectively, our findings suggest that GPR81 is critical for malignancy of breast cancer and may be a potential novel therapeutic target for breast carcinoma.

show abstract

“…The regulation of tumor microenvironment on OCPs or OCs has been deeply investigated in several tumors with high incidence of bone metastasis, such as breast cancer, lung cancer and prostate cancer (Aukes et al 2017 ; Grano et al 2000 ). Although our previous studies demonstrated that CRC cells could regulate osteoclastogenesis after bone metastasis of CRC (Zi-Chen et al 2020 ; Qian et al 2021 ), the process of how osteoclastogenesis is regulated by microenvironment of CRC is still far from clear.…”

Section: Introductionmentioning

confidence: 94%

IL4/IL4R signaling promotes the osteolysis in metastatic bone of CRC through regulating the proliferation of osteoclast precursors

Qian

Yang²,

Zhao

et al. 2021

Mol Med

View full text Add to dashboard Cite

Background Bone metastasis of colorectal cancer (CRC) often indicates a poor prognosis. Osteolysis can be observed in metastatic sites, implying an aberrant activation of osteoclasts. However, how osteoclastogenesis is regulated in metastatic microenvironment caused by colorectal cancer is still unclear. Methods In this study, mice bone metastatic model of CRC was established through injection of MC-38 or CT-26 cells. BrdU assays showed primary CD115 ( +) osteoclast precursors (OCPs) proliferated at the first 2 weeks. Transcriptomic profiling was performed to identify differentially expressing genes and pathways in OCPs indirectly co-cultured with CRC cells Results The expression of IL4Rα was found to be significantly upregulated in OCPs stimulated by tumor conditioned medium (CM). Further investigation indicated that IL-4 signaling regulated proliferation of OPCs through interacting with type I IL4 receptor, and neutrophils were the main source of IL-4 in bone marrow. The proliferation of OCPs can be inhibited in IL4 deficiency mice. In addition, ERK pathway was activated by IL4/IL4R signaling. Ravoxertinib, an ERK antagonists, could significantly prevent bone destruction through inhibiting the proliferation of OCPs. Conclusion Our study indicates the essential role of IL4/IL4R signaling for the proliferation of OCPs in early metastasis of CRC predominantly through activating ERK pathway, which remarkedly impacts the number of osteoclasts in later stage and leads to osteolytic lesions. Moreover, Ravoxertinib could be a new therapeutical target for bone metastasis of CRC.

show abstract

Lactic acid promotes metastatic niche formation in bone metastasis of colorectal cancer

Cited by 40 publications

References 48 publications

CCL7 playing a dominant role in recruiting early OCPs to facilitate osteolysis at metastatic site of colorectal cancer

CCL7 playing a dominant role in recruiting early OCPs to facilitate osteolysis at metastatic site of colorectal cancer

The lactate sensor GPR81 regulates glycolysis and tumor growth of breast cancer

IL4/IL4R signaling promotes the osteolysis in metastatic bone of CRC through regulating the proliferation of osteoclast precursors

Contact Info

Product

Resources

About