Page 330 - Read Online

Page 8 of 31 Paul J Cancer Metastasis Treat 2020;6:29 I http://dx.doi.org/10.20517/2394-4722.2020.63

Figure 4. Systemic hallmarks of cancer

metastasis influence, there is a permanent “trialogue” between the primary tumor, the metastatic sites and
the bone marrow [Figure 5]. Bone marrow can function as a source of hematogenic progenitor cells that
[62]
prepare the niche for metastasis [60,61] and, also possibly, as a source of malignant stem cells .

Bone marrow-derived cells (BMDCs), which are frequently recruited to sites of tissue injury and
[63]
inflammation, are crucial for the malignant process. In an elegant experiment, Houghton et al.
demonstrated that in some cases, BMDCs may even represent the origin of malignant cells. These findings
[64]
were subsequently confirmed by a different research team in a sarcoma mouse model .
[60]
Kaplan et al. pioneered the work on the metastatic niche by demonstrating that BMDCs that express
vascular endothelial growth factor receptor 1 (VEGFR-1) home to tumor-specific pre-metastatic sites
and form cellular clusters before the arrival of tumor cells. Besides, BMDCs that facilitate the growth of
tumor cells at distance from the site of origin and, cytokines and vesicles released into the circulation
[69]
also contribute to the development of distal metastasis [65-68] . In a recent review , a comprehensive list
of 34 primary-tumor, tumor stroma and myeloid derived factors that mobilize and recruit myeloid cells
directly from the bone marrow to the pre-metastatic niche was compiled. The authors also proposed
six characteristics of the pre-metastatic niche that empower the niche to favor tumor cell colonization
and promote metastasis: angiogenesis and vascular permeability, lymphangiogenesis, inflammation,