Page 64 - Read Online

Page 2 of 19 Maurizi et al. J Cancer Metastasis Treat 2021;7:35 https://dx.doi.org/10.20517/2394-4722.2021.74

[2]
research in the last century, metastatic cancer is still incurable . The occurrence of metastasis is a stepwise
[3]
process, in which cancer cells invade locally, enter the blood flow, and extravasate in a distal site . For this
process to happen, not only tumor cells need to acquire a specific set of “skills”, but also the tissue that will
be metastasized must change to allow tumor cell engraftment and growth. The fact that several types of
cancer show a predilection to a specific distal tissue has always been a key issue in cancer research, from the
[4]
days of the “seed and soil” theory of Dr. Paget to our time. The latest development in the field is the
conceptualization of the pre-metastatic niche (PMN). This is the phenomenon through which cancer cells
prepare the “soil” for their dissemination by secreting soluble mediators and exosomes to make it suitable
for their engraftment. Perhaps the most remarkable aspect of this process is that it could happen years
before overt metastases appear. Hence, the reprogramming of the microenvironment appears to be operated
by the tumor directly from the primary site before metastatic dissemination.

In cell biology, a niche is a specific area of a tissue, usually composed by few cells in close contact with each
other, working in tandem to achieve a specific function, together with the surrounding extracellular
matrix . Niches are very dynamic structures, at both the cellular and molecular levels, and they are able to
[5]
quickly integrate and adapt to external stimuli, providing an additional layer of regulation to especially
important processes, such as hematopoietic stem cells’ proliferation vs. quiescence. In fact, a deregulation in
such process may lead to severe consequences, including microenvironment-induced leukemogenesis or
stem cell exhaustion . The bone marrow microenvironment is the prototypical tissue where most of the
[6]
known niches have been discovered, and this should not come as a surprise, given that it presents much
more flexibility and degrees of freedom for resident and circulating cells to rearrange themselves in small,
specific groups compared to solid organs. 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 . In fact, the bone marrow is the site where the metastatic niche is most commonly established . The
[7]
[8]
mechanisms underlying the bone marrow PMN are very complex , and this is due to the fact that cellular
[9]
and molecular players may differ from one tumor to another, and that no spontaneous bone metastasis
models are currently available. The fact that the PMN is established early during tumor growth poses an
important challenge, as well as an opportunity: on the one hand, it means that circulating tumor cells
(CTCs) may be able to prime the microenvironment and engraft during the first stages of the disease, thus
making metastasis prevention a challenge. On the other hand, understanding the mechanisms inducing the
PMN formation may provide crucial molecular players which may be targeted to prevent homing and
metastatic growth in the bone marrow.

In this review, we describe the known cellular and molecular players in the bone/bone marrow PMN, as
well as the factors produced by both tumor and resident cells that allow CTCs homing into the bone/bone
marrow. Finally, we discuss possible therapeutic implications of the PMN in term of prevention of the
metastatic dissemination.

THE HALLMARKS OF THE BONE/BONE MARROW PRE-METASTATIC NICHE
[10]
Liu and Cao proposed six characteristics of the PMN influencing the fate of the CTCs upon arrival in the
secondary site. These are represented by immunosuppression, inflammation, angiogenesis, vascular
permeability, lymphangiogenesis, organotropism, and reprogramming. Their elegant description of this
phenomenon is generalizable to all PMNs; however, there are specific hallmarks that could be more
important than others in the bone/bone marrow PMN. Establishing an immunosuppressive niche is a
central strategy for tumor cells to overcome the immunosurveillance of the host. This process includes the
recruitment of immune and regulatory cells such as T cells Treg, macrophages, and myeloid-derived
suppressor cells in the PMN [11-13] .