Liquid Biopsy in Pre-Metastatic Niche: From Molecular Mechanism to Clinical Application

Abstract

Metastatic dissemination represents a hallmark of cancer that is responsible for the high mortality rate. Recently, emerging evidence demonstrates a time-series event—pre-metastatic niche (PMN) has a profound impact on cancer metastasis. Exosomes, cell-free DNA (cfDNA), circulating tumor cells (CTC), and tumor microenvironment components, as critical components in PMN establishment, could be monitored by liquid biopsy. Intensive studies based on the molecular profile of liquid biopsy have made it a viable alternative to tissue biopsy. Meanwhile, the complex molecular mechanism and intercellular interaction are great challenges for applying liquid biopsy in clinical practice. This article reviews the cellular and molecular components involved in the establishment of the PMN and the promotion of metastasis, as well as the mechanisms of their interactions. Better knowledge of the characteristics of the PMN may facilitate the application of liquid biopsy for clinical diagnosis, prognosis, and treatment.

Tumor-derived cell-free DNA and circulating tumor cells: partners or rivals in metastasis formation?

“…Indeed, the creation of a “metastatic niche” prior to the arrival of CTCs seems to be a key step in the metastatic cascade. This concept, known as PMN, is initiated by the primary tumors, which can secreted factors that can be organ-specific, thereby influencing metastatic organotropism [ 52 ]. Among these factors, exosomes and NETs play essential roles in PMN remodeling and both are associated with cfDNA in bodily fluids, although cfDNA can also exist independently [ 110 ].…”

“…This reprogramming may be initiated by factors secreted by the primary tumor prior to the arrival of CTCs in the metastatic niche. These factors can be organ-specific, thereby influencing metastatic organotropism [ 28 , 52 ].…”

“…Exosomes, in addition, hold significance in intercellular communication and the maintenance of cellular homeostasis [ 111 , 112 ]. Tumor-derived EVs, particularly exosomes, can play a role in ECM remodeling [ 113 ] and in PMN remodeling, inducing macrophage polarization in M2 state, an immunosuppressive microenvironment and stimulating angiogenesis [ 52 ]. These EVs can be used to predict organotropism, as specific organ metastases are associated with exosomal integrins such as α6β4 and α6β1 for lung metastases, and αvβ5 for liver metastases [ 114 ].…”

“…Nonetheless, this theory does have its limitations. Efficient secretion of tumoral EVs necessitates continuous release and acidic, hypoxic conditions [ 52 ]. Additionally, the effectiveness of HGT depends on the uptake capacity of recipient cells [ 132 ], which may render certain cells refractory to transformation [ 133 ].…”

Is cancer an intelligent species?

“…Thus, in contrast to the metastatic niche that is initiated and shaped upon arrival of cancer cells, the PMN is deficient in cancer cells but conducive to their tumor growth. Both tumor-secreted factors and tumor-shed extracellular vesicles (EVs) promote the evolution of PMNs through a sequence of events, starting from vascular leakiness to the alteration of local resident fibroblasts and the further recruitment of non-resident bone marrow-derived cells (BMDCs), finally attracting circulating tumor cells [ 77 ]. The establishment of PMNs facilitates metastasis by promoting CTC survival and outgrowth.…”