Contributed equally
Hepatocellular carcinoma (HCC) is a prevalent malignant tumor worldwide, with an unsatisfactory prognosis, although treatments are improving. One of the main challenges for the treatment of HCC is the prevention or management of recurrence and metastasis of HCC. It has been found that chemokines and their receptors serve a pivotal role in HCC progression. In the present review, the literature on the multifactorial roles of exosomes in HCC from PubMed, Cochrane library and Embase were obtained, with a specific focus on the functions and mechanisms of chemokines in HCC. To date, >50 chemokines have been found, which can be divided into four families: CXC, CX3C, CC and XC, according to the different positions of the conserved N-terminal cysteine residues. Chemokines are involved in the inflammatory response, tumor immune response, proliferation, invasion and metastasis via modulation of various signaling pathways. Thus, chemokines and their receptors directly or indirectly shape the tumor cell microenvironment, and regulate the biological behavior of the tumor. In addition, the potential application of chemokines in chemotaxis of exosomes as drug vehicles is discussed. Exosomes containing chemokines or expressing receptors for chemokines may improve chemotaxis to HCC and may thus be exploited for targeted drug delivery.
Hepatocellular carcinoma (HCC) is the sixth most common type of cancer worldwide and the third leading cause of cancer-associated death (
It has been found that chemokine networks may serve pivotal roles in inducing organ-specific metastasis (
The morbidity (>20 cases/100,000 population in East Asia) and mortality (95%) rates of HCC remain high, and there are ~782,000 new cases and 600,000 deaths worldwide per year (
Unlike CXCL12 and CXCL1, CXCL16 expression in the liver decreases when a tumor metastasizes to the liver (
As the only member of the CX3C chemokine subfamily, CX3CL1 is a transmembrane glycoprotein that exists in two forms: Membrane-bound and secretory. In addition, the mucin-like domain of CX3CL1 contains a cleavage site that allows metalloproteinases (such as ADAM10) to cleave and release proteins in a soluble form (
Among the four types of chemokines, there are two highly homologous XC chemokines: XC motif chemokine ligand 1 (XCL1) and XCL2, whose genes (SCYC1 and SCYC2, respectively) are located on chromosome 1. There are only two amino acid differences between them, and XCL1 is the variant with the predominant effect (
It has been demonstrated that XCR1+ DCs can promote the antitumor immune response and lead to tumor cell death (
The CC chemokine subfamily consists of >20 members, and the N-terminal of the members contain two adjacent cysteine residues (
CCL5 can bind to CCR1 and CCR3, but the activity of CCL5 is exerted by binding to CCR5 (
The CC subfamily is also associated with tumor drug resistance. In lung cancer, CCL2 is associated with docetaxel resistance via activation of the PI3K/Akt signaling pathway where it inhibits caspase3-dependent apoptosis (
Not all CC subfamily chemokines promote tumor progression. Gu
In summary, CC subfamily chemokines are increasingly considered to be involved in a variety of tumor biological processes, and are closely associated with the development, metastasis and regulation of the tumor microenvironment of HCC. However, further studies and novel techniques/therapeutics are required to improve the diagnosis and treatment of HCC effectively via regulation of CC subfamily chemokines.
In normal liver tissues, CXC chemokines are widely involved in the repair of hepatocyte injury by affecting hepatocyte proliferation and regeneration (
Studies have shown that neutrophils expressing CXCR2 chemotactically enter the liver by binding to CXCL1 (
The role of CXCL12 is very important in the development of HCC. In the past, it was considered that CXCR4 was the only receptor of CXCL12. CXCL12/CXCR4 binds specifically and is commonly involved in various pathophysiological processes, such as anti-apoptotic and angiogenesis processes (
CXCR3 is expressed in almost all cells, is upregulated in several types of primary and metastatic tumors (such as renal cancer, colon cancer and pulmonary metastasis tumor), and is considered to be essential for migration of cancer cells (
MDSCs regulate the immunosuppressive network and participate in all aspects of tumor progression, and their migration is associated with autocrine or paracrine chemokines (
Exosomes are microvesicles secreted by cells with a diameter of 30–100 nm (
Whether chemokines are expressed on the surface of exosomes, and whether they promote the chemotaxis of exosomes to HCC has been investigated. Viñas
There is an urgent need to identify novel therapeutic strategies for the management of HCC due to the poor prognosis of patients. In recent years, immunotherapy and molecular targeted therapy have become increasingly popular. However, the unique immune response in the liver favors tolerance, which represents a substantial challenge for conventional immunotherapy in patients with HCC (
In addition, exosomes, which mediate the transport of various proteins, DNA and RNA molecules, may be used as drug carriers; exosomes expressing chemokines can more effectively induce chemotaxis to specific lesions (
Not applicable.
The present review was supported by the Hebei Provincial Government Clinical Medicine Talents Training and Basic Research Project (grant no. 361003).
Not applicable.
DX and YZ wrote and reviewed the manuscript. DX, YL and JH designed the figures. DX, JH and JW edited the manuscript. DX, YZ and JW assessed all the raw data. YP and HT critically revised the manuscript. YL, YP and HT are responsible for confirming the authenticity of the data. All authors read and approved the final version of the manuscript.
Not applicable.
Not applicable.
The authors declare that they have no competing interests.
CXCL12/CXCR4 can induce angiogenesis, EMT and myeloid-derived suppressor cells to promote the progression of HCC. Additionally, CXCL12/CXCR4 expression enhances the activity of OV6+ liver cancer stem cells via the Wnt/β-catenin signaling pathway, thus enhancing invasion and migration of HCC. In addition, CXCL12/CXCR4 can directly promote HCC growth and metastasis. CXCL12, CXC motif chemokine ligand 12; CXCR4, CXC motif chemokine receptor 4; EMT, epithelial-mesenchymal transformation; HCC, hepatocellular carcinoma; OV6, oval cell marker.
Exosomes in targeted therapy of hepatocellular carcinoma. Exosomes expressing chemokine receptors enhance chemotaxis to target organs overexpressing corresponding chemokines. The present review hypothesized that the surface of hepatocellular carcinoma exosomes may be modified to overexpress chemokine receptors, such as CXCR4, and may be loaded with antitumor drugs, to enhance the chemotaxis of exosomes to hepatocellular carcinoma and achieve the goal of targeted therapy. CXCL12, CXC motif chemokine ligand 12; CXCR4, CXC motif chemokine receptor 4.
Chemokine families.
A, CXC chemokine family | |||||
---|---|---|---|---|---|
Chemokine receptors | Chemokines | Functions | Signaling pathways | Role in HCC | (Refs.) |
CXCR1 | CXCL6, | Chemotactic neutrophils | – | Up regulation of CXCL6 | ( |
CXCL7, | are involved in innate | transcription in HCC cells | |||
CXCL8 | immunity and acute | promotes HCC progression and | |||
inflammation | metastasis | ||||
PI3K/Akt | HCC plays an important role in | ( |
|||
invasion and metastasis | |||||
CXCR2 | CXCL1, | Chemotactic neutrophils | – | CXCR2-CXCL1 axis can regulate | ( |
CXCL2, | guide their migration to | neutrophil infiltration into HCC | |||
CXCL3, | inflammatory sites | tumor tissue | |||
CXCL5, | ERK1/2 | CXCL2 negatively regulates cell | ( |
||
CXCL6, | cycle in HCC cells; | ||||
CXCL7, | CXCL2 may play a key role in | ||||
CXCL8 | HCC metastasis | ||||
ERK1/2 | Overexpression of CXCL3 was | ( |
|||
significantly associated with tumor | |||||
capsule formation and vascular | |||||
invasion | |||||
PI3K/Akt/ | CXCR2/CXCL5 axis promotes | ( |
|||
GSK-3β/Snail | EMT of HCC cells; | ||||
CXCL5 can promote the invasion | |||||
and proliferation of hepatoma cells | |||||
by mediating the infiltration of | |||||
neutrophils | |||||
Akt/mTOR/ | HCC serves an important role in | ( |
|||
STAT3 | invasion and metastasis | ||||
CXCR3 | CXCL9, | It can promote the | MAPK | Promoting the invasion and | ( |
CXCL10, | migration of T cells, | metastasis of CD133 hepatoma | |||
CXCL11 | promote the interaction | cells | |||
between T cells and | c-Myc | CXCL10/CXCR3 signaling | ( |
||
antigen presenting | directly induces epithelioma | ||||
cells, and promote the | papulosum cyprinid | ||||
production of effector | mobilization, differentiation and | ||||
cells and memory cells | neovascularization, thus further | ||||
promoting tumor growth | |||||
ERK1/2 | Promoting the self-renewal and | ( |
|||
tumorigenicity of α2δ1 liver tumor | |||||
initiating cells | |||||
CXCR4 | CXCL12 | It participates in the migration of stem cells, stimulates the proliferation of B cells and bone marrow cells, and it is also involved in the process of HIV invading normal human cells. | PI3K/Akt | CXCL12 and its receptor CXCR4 promote EMT; Cancer cells decrease apoptosis and achieve self-renewal | ( |
CXCR5 | CXCL13 | Involved in B-cell | Wnt/β-catenin | CXCL13 serves an important role | ( |
homing in lymphoid | in the development of liver cancer | ||||
organs | and it may have clinical value in the diagnosis and prognosis of liver cancer | ||||
CXCR6 | CXCL16 | Promoting T-cell | Akt/mTOR | CXCL16 promotes HCC | ( |
migration | invasiveness and tumor | ||||
inflammatory environment | |||||
CXCR7 | CXCL11, | Regulating the | MAPK | Overexpression of CXCR7 | ( |
CXCL12 | development and | AKT | promotes the growth and invasion | ||
differentiation of B cells | of HCC; | ||||
It plays an important role in | |||||
promoting angiogenesis in liver cancer | |||||
CCR1 | CCL3, | Chemotactic T cells and | – | CCL3-CCR1 axis serves an | ( |
CCL5, | monocytes are involved | important role in the invasion and | |||
CCL7-8, | in innate and adaptive | metastasis of HCC by changing the | |||
CCL13, | immune response and | intracellular Ca concentration | |||
CCL14, | inflammatory response | PI3K/Akt | CCL5 induces cell growth, | ( |
|
CCL15, | migration and invasion; | ||||
CCL16, | Stimulating migration and invasion | ||||
CCL23 | of Huh7 hepatoma cells | ||||
Inhibition of | CCL14 is a prognostic biomarker | ( |
|||
Wnt/β-catenin | associated with immune invasion | ||||
in HCC | |||||
STAT3/Akt | It serves a key role in the | ( |
|||
metastasis of HCC | |||||
– | Low CCL23 expression is not | ( |
|||
conducive to the formation of | |||||
anti-tumor immune defense in | |||||
patients with liver cancer, which | |||||
significantly shortens the survival | |||||
time of patients with liver cancer | |||||
CCR2 | CCL2, | Mediating the expression | Hedgehog | Regulating tumor growth, | ( |
CCL7, | of inflammatory T-cell | metastasis and host immune | |||
CCL8, | cytokines induces | response to induce HCC cell | |||
CCL13 | macrophages and monocytes to recruit to inflammatory sites | invasion and EMT | |||
CCR3 | CCL5, | It serves an important | RhoB-VEGFA | It may promote the proliferation, | ( |
CCL7, | role in the regulation of | migration and invasion of HCC, | |||
CCL11, | eosinophil migration | promote lung metastasis and | |||
CCL15-16, | promote the formation of human | ||||
CCL24, | umbilical vein endothelial cells | ||||
CCL26 | |||||
CCR4 | CCL17, | Chemotactic T cells and | Wnt/β-catenin | CCL17 promotes the occurrence | ( |
CCL22 | monocytes migrate to the | of HCC | |||
skin and participate in | – | CCL22 contributes to Treg | ( |
||
allergic inflammation | recruitment and immunosuppression | ||||
ERK/Akt/MMP2 | CCR4 promotes HCC malignant | ( |
|||
tumor and HCC cell metastasis | |||||
CCR5 | CCL3, | Mediating the chemotaxis | – | Promoting tumor occurrence and | ( |
CCL4, | of macrophages and | development; | |||
CCL5, | T cells. Promoting HIV | PI3K/Akt/mTOR | It leads to the growth, proliferation | ( |
|
CCL8 | penetration into normal | and migration of hepatoma cells; | |||
human cells. | Regulating EMT and promoting | ||||
HCC metastasis | |||||
CCR6 | CCL20 | Dendritic cells, memory | STAT3 | It is involved in regulating the | ( |
T cells and Th17 cells | migration and invasion of HCC; | ||||
were chemotactic to | Tregs mediate the chemotaxis | ||||
inflammatory sites | of Tregs to the tumor | ||||
microenvironment and promote | |||||
liver cancer | |||||
CCR7 | CCL19, | It promotes the recycling | – | CCL19 may serve an inhibitory | ( |
CCL21 | of immature T cells, | role in the invasive regulation of | |||
and T cells homing to | human HCC | ||||
the secondary lymphoid | Akt-GSK3β | CCR7 promotes the development | ( |
||
tissue | of HCC and is associated with | ||||
poor survival | |||||
CCR8 | CCL1 | It is involved in T-cell | PKM2-ARRDC1 | CCL1/CCR8 axis promotes PKM2 | ( |
migration and Th2 | excretion in HCC cells | ||||
response and regulates | |||||
monocyte chemotaxis and | |||||
thymocyte apoptosis | |||||
CCR9 | CCL25 | Regulation of lymphocyte | – | It is concluded that the | ( |
epithelial interaction | regulation of multiple EMT | ||||
in small intestinal | markers serves an important | ||||
mucosa; Involved in | role in the migration and | ||||
multiple stages of adult | invasion of HCC cells, | ||||
T lymphocyte production | enhances the colony forming | ||||
ability of hepatoma cells and | |||||
their tumorigenicity, and is an | |||||
independent prognostic factor for | |||||
the overall survival of patients | |||||
with HCC | |||||
CCR10 | CCL27, | Key regulators of skin | PI3K/Akt | Inflammation drives | ( |
CCL28 | immune homeostasis; | hepatocarcinogenesis | |||
Regulating intestinal IgA | |||||
response and memory maintenance | |||||
CX3CR1 | CX3CL1 | Chemotactic lymphocytes | STAT3 | CX3CL1 stimulates chemotaxis | ( |
and macrophages; It also | Src/PTK2 | and cytotoxicity of CX3CR1 | |||
has a chemotactic effect | natural killer cells; | ||||
on microglia | CX3CL1 induces invasion and | ||||
migration of HCC cells into the spine | |||||
XCR1 | XCL1, | Establishment of | MAPK and | High XCR1 expression is | ( |
XCL2 | regulatory thymic | PI3K/Akt | positively associated with EMT, | ||
tolerance and production | which is closely associated with | ||||
of Tregs | tumor migration and invasion |
HCC, hepatocellular carcinoma; EMT, epithelial-mesenchymal transition; Tregs, regulatory T cells; Th, T helper; HIV, human immunodeficiency virus.