The Brain Pre-Metastatic Niche: Biological and Technical Advancements

Abstract

Metastasis, particularly brain metastasis, continues to puzzle researchers to this day, and exploring its molecular basis promises to break ground in developing new strategies for combatting this deadly cancer. In recent years, the research focus has shifted toward the earliest steps in the formation of metastasis. In this regard, significant progress has been achieved in understanding how the primary tumor affects distant organ sites before the arrival of tumor cells. The term pre-metastatic niche was introduced for this concept and encompasses all influences on sites of future metastases, ranging from immunological modulation and ECM remodeling to the softening of the blood–brain barrier. The mechanisms governing the spread of metastasis to the brain remain elusive. However, we begin to understand these processes by looking at the earliest steps in the formation of metastasis. This review aims to present recent findings on the brain pre-metastatic niche and to discuss existing and emerging methods to further explore the field. We begin by giving an overview of the pre-metastatic and metastatic niches in general before focusing on their manifestations in the brain. To conclude, we reflect on the methods usually employed in this field of research and discuss novel approaches in imaging and sequencing.

The origin of brain malignancies at the blood–brain barrier

“…Importantly, the pre-metastatic and metastatic niches both occur in the initial stages of metastatic development and although both niches conceptually follow one another, it is probable that their development and influence can occur both together and independently. As highlighted by Geissler and colleagues [ 69 ], the distinction between these niches is best viewed as a difference in function, with the pre-metastatic niche aiding in CTC access, anchorage, and early survival, while the metastatic niche promotes the survival, protection, and proliferation of DTCs. Pre-metastatic niche formation and its influence on metastatic invasion is described in detail for the liver [ 70 ], bone [ 71 ], lung [ 72 ], and lymph nodes [ 73 ].…”

“…In turn, such a niche has the potential to assist CTC invasion. Ultimately, the development of future techniques to experimentally define [ 69 ] and identify the development of a pre-metastatic niche in the brain could allow preemptive interventions to mitigate brain metastases [ 67 ].…”