The Roles of Stroma-Derived Chemokine in Different Stages of Cancer Metastases

Abstract

The intricate interplay between malignant cells and host cellular and non-cellular components play crucial role in different stages of tumor development, progression, and metastases. Tumor and stromal cells communicate to each other through receptors such as integrins and secretion of signaling molecules like growth factors, cytokines, chemokines and inflammatory mediators. Chemokines mediated signaling pathways have emerged as major mechanisms underlying multifaceted roles played by host cells during tumor progression. In response to tumor stimuli, host cells-derived chemokines further activates signaling cascades that support the ability of tumor cells to invade surrounding basement membrane and extra-cellular matrix. The host-derived chemokines act on endothelial cells to increase their permeability and facilitate tumor cells intravasation and extravasation. The tumor cells-host neutrophils interaction within the vasculature initiates chemokines driven recruitment of inflammatory cells that protects circulatory tumor cells from immune attack. Chemokines secreted by tumor cells and stromal immune and non-immune cells within the tumor microenvironment enter the circulation and are responsible for formation of a "pre-metastatic niche" like a "soil" in distant organs whereby circulating tumor cells "seed' and colonize, leading to formation of metastatic foci. Given the importance of host derived chemokines in cancer progression and metastases several drugs like Mogamulizumab, Plerixafor, Repertaxin among others are part of ongoing clinical trial which target chemokines and their receptors against cancer pathogenesis. In this review, we focus on recent advances in understanding the complexity of chemokines network in tumor microenvironment, with an emphasis on chemokines secreted from host cells. We especially summarize the role of host-derived chemokines in different stages of metastases, including invasion, dissemination, migration into the vasculature, and seeding into the pre-metastatic niche. We finally provide a brief description of prospective drugs that target chemokines in different clinical trials against cancer.

Keywords: cancer; chemokines; invasion; metastases; metastatic niche; stroma.

Figure 1

Schematic illustration of multifaceted roles of chemokines in invasion and dissemination. Chemokines bind to their receptors and regulate ECM remodeling, EMT, cell migration, and cell invasion.

Figure 2

Steps of metastases. (A) A cartoon of TME showing tumor cells invade ECM and migrate towards blood vessels. (B) At the blood vessels, tumor cells transmigrate across endothelial layer and become circulatory tumor cells (CTCs). (C) Tumor cells extravasate and seed into the lungs to generate metastatic foci. The dashed line inset diagram describes molecular events occurring at the time of transendothelial migration shown in (B) within dashed line box. The CAFs present in TME secrete CXCL12 that act on endothelial cells through receptor CXCR4 and decrease the expression of tight junction (TJ) molecules, which results in intravasation of tumor cells.

Figure 3

The schematic diagram showing different function of stromal-derived chemokines in pre-metastatic niche formation and metastases. Tumor cells along with stromal and immune cells in the primary tumor secrete several chemokines such as CCL2, CXCL12, CCL19, etc., that help in establishing the PMN in distant organs such as lung, liver, brain. Within the lungs SDF-1 and leukotrienes help in immune invasion. CCL2, CXCL12 aid in angiogenesis, form clots in blood vessels and help in survival of melanoma in the lung by inhibiting NK cell activity. In the brain, CCL19 acts on CCR7+ tumor cells and aid in their colonization. In the liver, CXCL12 along with TIMP1 and MIF help in neutrophil recruitment and deposition of fibronectin making liver tissue permissive for formation of a metastatic niche for circulating tumor cells.