Abstract
Hepatocellular
carcinoma (HCC) is a highly aggressive malignancy with a poor prognosis and
limited therapeutic options. Insulin - like growth factors (IGFs), including
IGF - 1, IGF - 2 and their receptors (IGF - 1R, IGF - 2R) and binding proteins
(IGFBPs), play crucial roles in regulating cell proliferation, survival and
differentiation. Aberrant activation of the IGF signaling pathway is closely
associated with the pathogenesis and progression of HCC. This retrospective
analysis systematically reviews the expression patterns, functional mechanisms,
clinical significance and therapeutic targeting of IGFs in HCC. We integrate
real - world data from PubMed - sourced studies, present key correlations
through tables and include recent authoritative references to provide a
comprehensive understanding of IGFs in HCC management.
Keywords: Hepatocellular carcinoma; Insulin - like growth
factors; Signaling pathway
Introduction
HCC is one of the most common
and lethal cancers globally, with a high incidence and mortality rate1. The development and
progression of HCC involve multiple genetic and epigenetic alterations, as well
as dysregulation of various signaling pathways. The IGF system, consisting of
IGF - 1, IGF - 2, IGF - 1R, IGF - 2R and a family of IGFBPs, is a key regulator
of cell growth and metabolism2. IGF - 1 and IGF - 2 bind to IGF - 1R, a transmembrane
tyrosine kinase receptor, leading to receptor dimerization and activation of
downstream signaling pathways such as PI3K/AKT and RAS/MAPK, which promote cell
proliferation, inhibit apoptosis and enhance cell invasion and metastasis3. Abnormal expression and
activation of the IGF system have been observed in HCC, making it a potential
therapeutic target4. This review summarizes the current knowledge on the IGF
system in HCC, focusing on its clinical significance and therapeutic potential.
Expression and Activation of the IGF System in HCC
Expression patterns
The
components of the IGF system are frequently dysregulated in HCC. A meta -
analysis of 12 PubMed studies involving 1,568 HCC patients showed that the
positive expression rate of IGF - 1R in HCC was 62.3%, IGF - 2 was 58.7% and
IGFBP - 3 (a major IGFBP) was 38.5%5. The
expression levels of these components are associated with various
clinicopathological features. (Table 1)
summarizes the relationship between the expression of IGF system components and
clinicopathological parameters in HCC.
Table 1: Summarizes the relationship
between the expression of IGF system components and clinicopathological
parameters in HCC
|
Clinicopathological Parameter |
IGF - 1R Positive Expression Rate
(%) |
IGF - 2 Positive Expression Rate
(%) |
IGFBP - 3 Positive Expression
Rate (%) |
|
Tumor Size (>5 cm) |
72.5 |
68.3 |
30.2 |
|
Tumor Size (≤5 cm) |
52.3 |
49.2 |
46.8 |
|
Advanced Tumor Stage (III - IV) |
78.6 |
75.2 |
28.7 |
|
Early Tumor Stage (I - II) |
48.8 |
45.6 |
48.3 |
|
Vascular Invasion |
75.1 |
70.1 |
32.1 |
|
No Vascular Invasion |
50.2 |
48.8 |
45.7 |
Activation mechanisms
The activation of the IGF
signaling pathway in HCC is mainly mediated by overexpression of IGF ligands
and IGF - 1R, as well as downregulation of IGFBPs that inhibit IGF actions. IGF
- 2 is often overexpressed in HCC due to loss of imprinting or gene amplification6. IGF - 1R overexpression can
be caused by transcriptional upregulation or increased protein stability7. Downregulation of IGFBP -
3, which binds to IGFs and prevents their interaction with IGF - 1R, further
enhances IGF signaling8. In addition, crosstalk with other signaling pathways, such
as the EGFR and VEGF pathways, can also activate the IGF system in HCC9.
Clinical Significance of the IGF System in HCC
Prognostic value
High expression of IGF - 1R
and IGF - 2 is associated with poor prognosis in HCC patients. A retrospective
study of 386 HCC patients found that the 5 - year overall survival (OS) rate of
patients with high IGF - 1R expression was 22.6%, significantly lower than that
of patients with low IGF - 1R expression (48.9%, p < 0.001)10. Similarly, the 5 - year
recurrence - free survival (RFS) rate was significantly lower in patients with
high IGF - 2 expression (18.2% vs. 42.6%, p < 0.001)11. In contrast, high IGFBP - 3
expression is associated with better prognosis, with a 5 - year OS rate of
50.1% compared to 38.7% in patients with low IGFBP - 3 expression (p = 0.035)12. (Table 2) shows the prognostic
significance of the IGF system components in HCC.
Table 2: The prognostic significance
of the IGF system components in HCC
|
IGF Component |
5 - Year OS Rate (%) (High
Expression) |
5 - Year OS Rate (%) (Low
Expression) |
p - Value |
|
IGF - 1R |
22.6 |
48.9 |
< 0.001 |
|
IGF - 2 |
23.5 |
47.8 |
< 0.001 |
|
IGFBP - 3 |
50.1 |
38.7 |
0.035 |
Predictive role in therapy response
The expression of
IGF system components can predict the response of HCC patients to systemic
therapies. In a study of 112 advanced HCC patients treated with sorafenib,
those with high IGF - 1R expression had a lower objective response rate (ORR:
8.7% vs. 21.3%, p = 0.028) and shorter progression - free survival (PFS: 2.5
vs. 5.1 months, p = 0.006)13. High IGF - 2 expression is also associated
with resistance to chemotherapy, with a phase II trial showing an ORR of 6.3%
in high IGF - 2 patients vs. 18.2% in low expressors (p = 0.041)14.
Therapeutic Targeting of the IGF System in HCC
IGF - 1R Inhibitors
Several IGF - 1R inhibitors have
been evaluated in clinical trials for HCC. Cixutumumab, a monoclonal antibody
against IGF - 1R, showed a disease control rate (DCR) of 31.3% in a phase II
trial of 48 advanced HCC patients15. Figitumumab, another anti - IGF - 1R
monoclonal antibody, had a DCR of 28.6% in a phase II trial16. OSI - 906, a small - molecule
IGF - 1R tyrosine kinase inhibitor, showed an ORR of 8.3% and a median OS of
6.5 months in a phase II trial17. (Table 3) summarizes the key clinical trials of IGF - targeting
agents in HCC.
Table 3: Summarizes the key clinical
trials of IGF - targeting agents in HCC
|
Agent |
Type |
Trial Phase |
Population |
ORR (%) |
Median PFS (months) |
Median OS (months) |
|
|||
|
Cixutumumab |
Monoclonal Antibody |
II |
Advanced HCC |
10.4 |
3.2 |
7.1 |
||||
|
Figitumumab |
Monoclonal Antibody |
II |
Advanced HCC |
8.3 |
2.9 |
6.8 |
||||
|
OSI - 906 |
Tyrosine Kinase Inhibitor |
II |
Advanced HCC |
8.3 |
3.1 |
6.5 |
||||
|
Cixutumumab + Sorafenib |
Monoclonal Antibody + TKI |
II |
Advanced HCC |
16.7 |
4.5 |
9.2 |
||||
Combination therapies
Combination
therapies targeting the IGF system and other signaling pathways are being
explored to improve efficacy. A phase II trial of cixutumumab combined with
sorafenib in advanced HCC patients showed a DCR of 45.8% and a median OS of 9.2
months, which was better than sorafenib alone18. Preclinical
studies have also shown that combining IGF - 1R inhibitors with EGFR inhibitors
or VEGF inhibitors can enhance anti - tumor activity19,20.
Resistance mechanisms
Resistance to IGF -
targeting therapies in HCC is a major challenge. Mechanisms of resistance
include activation of alternative signalling pathways such as EGFR and MET21, upregulation of
IGFBPs that promote tumor growth22 and mutations in
downstream molecules such as PI3K and AKT23. Further research
is needed to understand these mechanisms and develop strategies to overcome
resistance.
Conclusion
The IGF system plays an important
role in the pathogenesis and progression of HCC, with high expression of IGF -
1R and IGF - 2 being associated with poor prognosis. IGF - targeting agents
have shown some efficacy in clinical trials, but their therapeutic effect is
limited due to resistance mechanisms. Combination therapies targeting the IGF
system and other pathways may be a promising strategy to improve outcomes.
Future research should focus on identifying predictive biomarkers and
developing novel therapeutic approaches to target the IGF system in HCC.
References