Crosstalk between cancer cells and tumor associated macrophages is required for mesenchymal circulating tumor cell-mediated colorectal cancer metastasis

Abstract

Background Tumor-associated macrophages (TAMs) are major components of tumor microenvironment that frequently associated with tumor metastasis in human cancers. Circulating tumor cell (CTC), originating from primary tumor sites, is considered to be the precursors of tumor metastasis. However, the regulatory mechanism of TAMs in CTC-mediated tumor metastasis still remains unclear. Methods Immunohistochemical staining was used to detect the macrophages infiltration (CD68 and CD163), epithelial–mesenchymal transition (EMT) markers (E-cadherin and Vimentin) expression in serial sections of human colorectal cancer (CRC) specimens. Then, the correlations between macrophages infiltration and clinicopathologic features, mesenchymal CTC ratio, and patients’ prognosis were analyzed. A co-culture assay in vitro was used to evaluate the role of TAMs on CRC EMT, migration and invasion, and ELISA, luciferase reporter assay and CHIP were performed to uncover the underlying mechanism. Furthermore, an in vivo model was carried out to confirm the effect of TAMs on mesenchymal CTC-mediated metastasis. Results Clinically, CD163 + TAMs infiltrated in invasive front was associated with EMT, mesenchymal CTC ratio, and poor prognosis in patients with CRC. CRC–conditioned macrophages regulated EMT program to enhance CRC cells migration and invasion by secreting IL6. TAMs-derived IL6 activated the JAK2/STAT3 pathway, and activated STAT3 transcriptionally inhibited the tumor suppressor miR-506-3p in CRC cells. miR-506-3p, a key miRNA regulating FoxQ1, was downregulated in CRC cells, resulting in increased FoxQ1 expression, which in turn led to the production of CCL2 that promoted macrophage recruitment. Inhibition of CCL2 or IL6 broke this loop and reduced macrophage migration and mesenchymal CTC-mediated metastasis, respectively. Conclusions Our data indicates that TAMs induce EMT program to enhance CRC migration, invasion, and CTC-mediated metastasis by regulating the JAK2/STAT3/miR-506-3p/FoxQ1 axis, which in turn leads to the production of CCL2 that promote macrophage recruitment, revealing a new cross-talk between immune cells and tumor cells in CRC microenvironment. Electronic supplementary material The online version of this article (10.1186/s12943-019-0976-4) contains supplementary material, which is available to authorized users.

The establishment of immune infiltration based novel recurrence predicting nomogram in prostate cancer

“…Tumor‐infiltrating immune cells (TIICs) are essential components of the tumor microenvironment and can alter the immune status of the tumor. Several studies have demonstrated therapeutic strategies against tumors by targeting TIICs . Clinical outcomes and the potential mechanisms involving PCa and TIICs have been widely reported.…”

“…Several studies have demonstrated therapeutic strategies against tumors by targeting TIICs. [15][16][17][18][19] Clinical outcomes and the potential mechanisms involving PCa and TIICs have been widely reported. Kaur et al 20 marked the T cells in PCa tissues with CD3, CD8, and FOXP3 immunostaining and revealed that ERG activity and PTEN loss were affected by the high proportion of T cells, but clinical outcomes showed no association with these results.…”

CD2AP inhibits metastasis in gastric cancer by promoting cellular adhesion and cytoskeleton assembly

“…Accumulating evidence indicates that DGC metastasis is closely related to alterations in the expression of cancer cell adhesion‐associated and cytoskeleton proteins. Cell‐to‐cell adhesion is critical for the maintenance of normal tissue morphogenesis and homeostasis, 6 and in other cellular processes such as differentiation, survival, and migration, which are controlled by the activation of gene expression and signaling pathways 31 . E‐cadherin, which is involved in the formation of cell‐cell adherent junctions that define the differentiation and proliferation of epithelial cells and suppression of invasion has been identified as an important tumor suppressor in GC 32–35 .…”

“…Despite great progress in identifying novel therapeutic targets for advanced or metastatic GC, the underlying molecular mechanisms are poorly understood, in part because of the biological heterogeneity of GC 5 . However, accumulating evidence indicates that a reduction of intercellular adhesion and alterations in the cytoskeleton structure are the major causes of the development of GC 6 . Moreover, several studies have shown that the intercellular adhesion‐related molecules such as E‐cadherin, ZO‐1, CAPZA1, and SCIN can impact the prognosis of cancer patients 7–9 .…”

“…5 However, accumulating evidence indicates that a reduction of intercellular adhesion and alterations in the cytoskeleton structure are the major causes of the development of GC. 6 Moreover, several studies have shown that the intercellular adhesion-related molecules such as E-cadherin, ZO-1, CAPZA1, and SCIN can impact the prognosis of cancer patients. [7][8][9] Thus, identifying novel molecules or mutations involved in GC-related intercellular adhesion or cytoskeleton assembly is an important step for understanding the pathogenesis of GC metastasis.…”