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Page 4 of 19 Maurizi et al. J Cancer Metastasis Treat 2021;7:35 https://dx.doi.org/10.20517/2394-4722.2021.74

Table 1. Cell types and factors involved in the bone PMN formation
Cell type Molecules Target(s) Function
Primary tumour Tumour cells PTHrP Osteoblasts Acts on Osteoblasts inducing the RANKL and CCL2
expression
MINDIN Osteoblasts Increase osteoclastogenesis and tumour cell adhesion
on osteoblasts and bone
LOX Osteoblasts Induce bone matrix remodelling establishing a
permissive environment for tumour cels
HPSE Osteoblasts Acts on Osteoblast inducing the RANKL expression
IL8 Osteoclast precursors Activate osteoclastogenesis
Syndecan1
SAA1/3 Immune cells and Recruitment of immune and regulatory cells in the
TLR4 osteoclasts PMN, as well as enhance osteoclastogenesis
TNFα
Il6
Integrin αvβ3 Bone matrix Enhances the homing of tumour cells into bone
CXCR4 Tumour cells Promotes bone homing and colonization
Bone/Bone marrow Osteoblasts RANKL Osteoclasts precursors Activate osteoclastogenesis
microenvironment CCL2 M2 Macrophages Recruits and activates M2 macrophages
SDF1 Tumour cells Enhances the homing of tumour cells into bone
DKK1
Osteoclasts IGF-1 Tumour cells and Growth factors stimulating tumour growth and
(Activity) BMPs bone/bone marrow microenvironmental changes in bone/bone marrow
PDGF cells
TGFβ
Osteocytes CCL12 Tumour cells Enhances the homing of tumour cells into bone
IL6 Tumour cells Affect the homing and the cancer cells proliferation in
HFG bone/bone marrow microenvironment
HIF-1
GDF15 Tumour cells Enhances cancer cells invasion and growth through the
growth response 1 (EGR1) transcription factor-
mediated mechanisms
Notch Tumour cells Mediate cell-cell communication
VEGF Endothelial cells Increase vascular permeability
BMP7
Sclerostin
RANKL Endothelial cells and Increase vascular permeability and osteoclastogenesis
osteoclasts
Bone marrow Inteleukines Endothelial and tumour Induce vascular leakiness
adipocytes (6,1β) cells
(BMAs) TNFα
ANGPTL2/4
Visfatin
SDF1
Endothelial cells VCAM-1 Tumour cells Enhances the vascular adhesion and the homing of
Integrin α4β1 tumour cells into bone
Immune cells RANKL Osteoclasts Activate osteoclastogenesis
IL17F

PTHrP: Parathyroid hormone-related peptide; LOX: lysil oxidase; HPSE: heparanase; SAA1: serum amyloid A1; SAA3: serum amyloid A3; TLR4:
toll-like receptor 4; TNF: tumor necrosis factor; RANKL: receptor-activator of nuclear factor κB ligand; CCL2: CC-motif chemochine ligand 2; SDF1:
stromal cell-derived factor 1; DKK1: Dikkopf-related protein 1; IGF-1: insulin-like growth factor-1; BMPs: bone morphogenic proteins; PDGF:
platelet-derived growth factor; HIF-1: hypoxia inducible factor 1; GDF15: growth-derived factor 15; VEGF: vascular endothelial growth factor; SDF1:
stromal cell-derived factor 1; VCAM-1: vascular cell adhesion molecule 1.

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unsuccessful . Therefore, PTHrP, HPSE, and its derivatives IL-8 and Syndecan-1 can start the vicious cycle
directly from the primary site and prime the bone microenvironment to metastasis by increasing the
osteoclast differentiation and bone resorption.