Hypoxic colorectal cancer cells promote metastasis of normoxic cancer cells depending on IL-8/p65 signaling pathway

Yulong Mi,Chang Yan,Jichao Qin,Chensen Ma,Yibing Hu,Hui Zhao,Xiaolan Li,Deding Tao,Kaiyu Huang,Lei Mu

doi:10.1038/s41419-020-02797-z

Yulong Mi, Chang Yan + Show 8 more

Open Access

https://doi.org/10.1038/s41419-020-02797-z

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Abstract

Tumor heterogeneity is an important feature of malignant tumors, and cell subpopulations may positively interact to facilitate tumor progression. Studies have shown that hypoxic cancer cells possess enhanced metastatic capacity. However, it is still unclear whether hypoxic cancer cells may promote the metastasis of normoxic cells, which have greater access to the blood circulation. When cocultured with hypoxic CRC cells or treated with hypoxic CRC cell-derived CM, normoxic CRC cells possessed increased metastatic capacity. Furthermore, hypoxic CRC cell-derived CM was enriched in interleukin 8. Hypoxic CRC cell-derived CM and recombinant human IL-8 both enhanced the metastatic capacity of normoxic cells by increasing the phosphorylation of p65 and then by inducing epithelial-mesenchymal transition. Knockdown of IL-8 in hypoxic CRC cells or the use of an anti-IL-8 antibody attenuated the CM- or rhIL-8-induced prometastatic capacity of normoxic CRC cells. Inhibition or knockdown of p65 abrogated IL-8-induced prometastatic effects. Most importantly, hypoxia-treated xenograft tumors enhanced the metastasis of normoxic CRC cells. Hypoxic CRC cell-derived IL-8 promotes the metastatic capacity of normoxic cells, and novel therapies targeting the positive interactions between hypoxic and normoxic cells should be developed.

Highlights

Colorectal cancer (CRC) is the third most common cause of cancer-associated mortality worldwide, and CRC patients typically die due to metastatic lesions[1]
Hypoxic CRC cells possess higher metastatic capacity than normoxic CRC cells Considering that hypoxic areas have low oxygen and a deficient serum supply, hypoxia in solid tumors is a chronic condition[3,4]
We found that HSS CRC cells expressed higher mRNA levels of matrix metalloproteinase, such as MMP1, MMP2, and membrane type 1-matrix metalloproteinase 1 (MT1MMP) than normoxic CRC cells (i.e., Control) (Fig. S1B)

Summary

Introduction

Colorectal cancer (CRC) is the third most common cause of cancer-associated mortality worldwide, and CRC patients typically die due to metastatic lesions[1]. Tumor heterogeneity results from tumor cells themselves, and from different tumor microenvironments, such as those resulting from the maldistribution of blood vessels[2,3,4]. Official journal of the Cell Death Differentiation Association. Mi et al Cell Death and Disease (2020)11:610 from bone marrow, which contribute to vascular heterogeneity[5]. Inadequate function of poorly organized tumor vasculatures results in areas of hypoxia and limited nutrient supply, which can generate distinct microenvironments within the tumor and contribute to interand intratumor heterogeneity to influence the clinical outcome. There is accumulating evidence that, in addition to their mutual interactions, tumor cells cooperate to promote tumor progression, recurrence, and metastasis[2,6]. Due to the cooperation of tumor cells, increased tumor heterogeneity may lead to a worse prognosis[6]

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