Source: Sun Yat-sen Memorial Hospital
Written by: Sun Yat-sen Memorial Hospital
Edited by: Wang Dongmei

The research group of Prof. Song Erwei from Sun Yat-sen Memorial Hospital, Sun Yat-sen University has made a breakthrough in the research of breast cancer metastasis, demonstrating the interaction between cancer cells with EMT(“the seeds”) and TAMs (“the soil”) . The results of this study were published in the journal Cancer Cell on May 12th, 2014.

Breast cancer remains the most common malignancy in women worldwide and is the leading cause of cancer-related mortality. Despite the significant improvements in both diagnosis and therapy for breast cancer patients, metastasis still consists of the major course of mortality.
 
More than 100 years ago, Stephen Paget’s proposed that metastasis depend on cross-talk between selected cancer cells (“the seeds”) and the specific organ microenvironments (“the soil”). It’s well established that tumor associated macrophages (TAMs), the key orchestrator of tumor microenvironment (“the soil”), promote tumor metastasis. In addition, studies indicate cancer cells (“the seeds”) can actively modulate tumor microenvironment.

It has been reported that Epithelial-mesenchymal transition (EMT) of cancer cells, a process associated with metastasis, is frequently observed at the invasive front of advanced tumors, where TAMs are usually found. However, the interaction between cancer cells with EMT(“the seeds”) and TAMs (“the soil”) remains to be elucidated.

With five-year research, Ph.D candidate Su shicheng, instructed by Prof. Song Erwei and Prof. Liu Qiang demonstrates Mesenchymal-like breast cancer cells activate macrophages to a TAM-like phenotype, mediated by cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF). On the other hand, GM-CSF-activated macrophages induce EMT of breast cancer cells via CCL18, forming a positive feedback loop. This GM-CSF-CCL18 loop promotes EMT and metastasis of breast cancer cells both in coculture systems and in humanized mouse model. Furthermore, break of this positive feedback loop via inhibiting GM-CSF or CCL18 reduces breast cancer metastasis. Also, the GM-CSF-CCL18 loop is associated with EMT, triple-negative subtype, metastasis, and poor prognosis in breast cancer patients.

This study is a spotlight on cancer research, showing the GM-CSF-CCL18 loop plays an essential role in cancer metastasis, suggesting the feedback loop between tumor microenvironment and cancer cells could be a therapeutic target or diagnosis indicators for cancer metastasis, different from the previous study focused on cancer cells.

Prof. Song Erwei is the correspondence author. This work was supported by grants from 973 Projects from the Ministry of Science and Technology of China, the Natural Science Foundation of China, the National S&T Major Special Project on New Drug Innovation of China, the Science Foundation of Guangdong Province, the Translational Medicine Public Platform of Guangdong Province, and the Ministry of Education of China.

The link to the paper: www.cell.com/cancer-cell/abstract/S1535-6108(14)00127-5