Pre-metastatic niche: from revealing the molecular and cellular mechanisms to the clinical applications in breast cancer metastasis

Abstract

Breast cancer (BC) is one of the most commonly diagnosed cancers and the leading cause of cancer-related deaths in women worldwide. Metastasis is a major contributor to high cancer mortality and is usually the endpoint of a series of sequential and dynamic events. One of the critical events is forming a pre-metastatic niche (PMN) that occurs before macroscopic tumor cell invasion and provides a suitable environment for tumor cells to colonize and progress into metastases. Due to the unique characteristics of PMN in cancer metastasis, developing therapies to target PMN may bring new advantages in preventing cancer metastasis at an early stage. Various biological molecules, cells, and signaling pathways are altered in BC, regulating the functions of distinctive immune cells and stromal remodeling, inducing angiogenesis, and effect metabolic reprogramming and organotropism to promote PMN formation. In this review, we elucidate the multifaceted mechanisms contributing to the development of PMN in BC, discuss the characteristics of PMN, and highlight the significance of PMN in providing potential diagnostic and therapeutic strategies for BC metastasis, which may bring promising insights and foundations for future studies.

Figure 1

Functions of the PMN in tumor metastasis. The formation of PMN promotes tumor metastasis in several phases.①Initiation phase (remote control of primary tumors): Primary tumors produce soluble factors that induce the formation of a non-mature tumor pre-metastatic microenvironment; ②Recruiting phase: BMDCs and a variety of immunomodulatory cells are constantly recruited to specific sites, where they interact with stromal cells here to change the local microenvironment, forming a mature PMN; ③Licensing phase (preparation of the microenvironment): allow CTCs to reach and colonize; ④Metastatic phase: massive CTCs colonize and grow, and gradually form visible metastasis. The figure was created using Biorender (https://biorender.com/).

Figure 2

Characteristics and related mechanisms of PMN in BC. An overview of the characteristics and related mechanisms of PMN in BC can be summarized as follows: regulation of immune cells, stromal remodeling, angiogenesis and vascular permeability, metabolic reprogramming, and organotropism. The figure was created using Biorender (https://biorender.com/).

Figure 3

Regulation of immune cells in PMN in BC. During the formation of PMN in BC, immune cells such as MDSCs, neutrophils, macrophages, and regulatory T/B lymphocytes are recruited, regulated and modified via different mechanisms and signaling pathways, which promote the colonization of tumor cells and further metastasis. The figure was created by Figdraw (https://www.figdraw.com/).

Figure 4

Therapeutic strategies targeting the PMN in BC. Several therapeutic options, such as targeting signaling pathways mediated by immune cells, stromal remodeling, vascular destabilization, and targeting organotropism, may prevent PMN formation and further metastasis in BC. The figure was created using Biorender (https://biorender.com/).