Characteristics of pre-metastatic niche: the landscape of molecular and cellular pathways

Abstract

Metastasis is a major contributor to cancer-associated deaths. It involves complex interactions between primary tumorigenic sites and future metastatic sites. Accumulation studies have revealed that tumour metastasis is not a disorderly spontaneous incident but the climax of a series of sequential and dynamic events including the development of a pre-metastatic niche (PMN) suitable for a subpopulation of tumour cells to colonize and develop into metastases. A deep understanding of the formation, characteristics and function of the PMN is required for developing new therapeutic strategies to treat tumour patients. It is rapidly becoming evident that therapies targeting PMN may be successful in averting tumour metastasis at an early stage. This review highlights the key components and main characteristics of the PMN and describes potential therapeutic strategies, providing a promising foundation for future studies.

Exosomes and Brain Metastases: A Review on Their Role and Potential Applications

“…The discovery of the PMN establishment prior to circulating tumor cells (CTCs) arrival at metastatic sites paved the way for numerous research studies focused not only on the molecular drivers of such process, but also on the molecular and cellular alteration occurring during this process and it is now possible to find several excellent reviews on this matter [ 26 , 52 , 58 , 59 ]. Overall, a PMN consists of a series of events, namely vascular leakiness, alteration of local resident cells, recruitment of non-resident cells, extracellular matrix (ECM) remodeling and immune deregulation [ 52 , 60 ]. All these events are induced by tumor-secreted factors and EVs, including exosomes [ 52 , 60 ].…”

“…Overall, a PMN consists of a series of events, namely vascular leakiness, alteration of local resident cells, recruitment of non-resident cells, extracellular matrix (ECM) remodeling and immune deregulation [ 52 , 60 ]. All these events are induced by tumor-secreted factors and EVs, including exosomes [ 52 , 60 ].…”

How the “seed” prepares the “soil”: the bone/bone marrow pre-metastatic niche

“…Their role, albeit less well-described, seems to also be pivotal in the establishment of the PMN in the bone/bone marrow compartment. Osteoblasts have been shown to respond to primary tumor-secreted factors such as PTHrP, which activates their RANKL production and increases osteoclast differentiation, thus starting a classic cancer-bone "vicious cycle" at a distance [8] . This activation of osteoclastic bone resorption triggers the release of factors such as insulin-like growth factor-1, bone morphogenic proteins, and platelet-derived growth factor from the bone matrix, which may help establish a pre-metastatic microenvironment.…”

“…It has been demonstrated that the TGFβ released upon tumor-induced bone resorption is able to increase invasion, chemotaxis, and angiogenesis [105][106][107] . Moreover, TGFβ stimulates tumor cells to produce osteolytic factors that enhance osteoclast activity, eventually leading to increased bone resorption [8,18] . This further increases the release of TGFβ from the bone matrix, fueling the so-called "vicious cycle" in the bone microenvironment.…”

“…Of note, this microenvironment is also a frequent site of metastasis for the most common human cancers, including breast, prostate, ovarian, colon, liver, and lung [7] . In fact, the bone marrow is the site where the metastatic niche is most commonly established [8] . The mechanisms underlying the bone marrow PMN are very complex [9] , and this is due to the fact that cellular and molecular players may differ from one tumor to another, and that no spontaneous bone metastasis models are currently available.…”