The insulin-like growth factor (IGF) axis as an anticancer target in prostate cancer

Heidegger, Isabel; Massoner, Petra; Sampson, Natalie; Klocker, Helmut

doi:10.1016/j.canlet.2015.07.026

Cited by 47 publications

(47 citation statements)

References 104 publications

(118 reference statements)

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“…The IGF-1R has emerged as a molecule with important roles in cancer biology (7) and is overexpressed in a high percentage of primary and metastatic tumors, including PCa (4, 5, 7, 70). Most of the studies on IGF-1R signaling have focused on its role in the differential activation of two important intracellular signaling pathways: the MAPK-ERK pathway, which regulates cell proliferation, differentiation, and tissue homeostasis, or the PI3K-AKT cascade, which promotes cell survival, metabolism, antiapoptosis, and differentiation (6, 71).…”

Section: Discussionmentioning

confidence: 99%

PSMA redirects cell survival signaling from the MAPK to the PI3K-AKT pathways to promote the progression of prostate cancer

et al. 2017

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Increased abundance of the prostate-specific membrane antigen (PSMA) on prostate epithelium is a hallmark of advanced metastatic prostate cancer (PCa) and correlates negatively with prognosis. However, direct evidence that PSMA functionally contributes to PCa progression remains elusive. We generated mice bearing PSMA-positive or PSMA-negative PCa by crossing PSMA-deficient mice with transgenic PCa (TRAMP) models, enabling direct assessment of PCa incidence and progression in the presence or absence of PSMA. Compared with PSMA-positive tumors, PSMA-negative tumors were smaller, lower-grade, and more apoptotic with fewer blood vessels, consistent with the recognized proangiogenic function of PSMA. Relative to PSMA-positive tumors, tumors lacking PSMA had less than half the abundance of type 1 insulin-like growth factor receptor (IGF-1R), less activity in the survival pathway mediated by PI3K-AKT signaling, and more activity in the proliferative pathway mediated by MAPK-ERK1/2 signaling. Biochemically, PSMA interacted with the scaffolding protein RACK1, disrupting signaling between the β1 integrin and IGF-1R complex to the MAPK pathway, enabling activation of the AKT pathway instead. Manipulation of PSMA abundance in PCa cell lines recapitulated this signaling pathway switch. Analysis of published databases indicated that IGF-1R abundance, cell proliferation, and expression of transcripts for antiapoptotic markers positively correlated with PSMA abundance in patients, suggesting that this switch may be relevant to human PCa. Our findings suggest that increase in PSMA in prostate tumors contributes to progression by altering normal signal transduction pathways to drive PCa progression and that enhanced signaling through the IGF-1R/β1 integrin axis may occur in other tumors.

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Section: Discussionmentioning

confidence: 99%

PSMA redirects cell survival signaling from the MAPK to the PI3K-AKT pathways to promote the progression of prostate cancer

et al. 2017

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“…Several preclinical studies have indicated the importance of the IGF axis for PCa progression and provided the basis for clinical trials with the IGF-1R as an anti-cancer target, alone or in combination with conventional therapies (recently reviewed in [23]). Reciprocal activation has been observed between the IGF-1R and the AR signaling pathways, supporting the rationale of simultaneous inhibition in cancer treatment [24, 25].…”

Section: Discussionmentioning

confidence: 99%

Inhibition of the insulin-like growth factor-1 receptor potentiates acute effects of castration in a rat model for prostate cancer growth in bone

Nordstrand

Bergström

Thysell

et al. 2017

Clin Exp Metastasis

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Prostate cancer (PCa) patients with bone metastases are primarily treated with androgen deprivation therapy (ADT). Less pronounced ADT effects are seen in metastases than in primary tumors. To test if acute effects of ADT was enhanced by concurrent inhibition of pro-survival insulin-like growth factor 1 (IGF-1), rats were inoculated with Dunning R3327-G tumor cells into the tibial bone marrow cavity and established tumors were treated with castration in combination with IGF-1 receptor (IGF-1R) inhibitor NVP-AEW541, or by each treatment alone. Dunning R3327-G cells were stimulated by androgens and IGF-1 in vitro. In rat tibia, Dunning R3327-G cells induced bone remodeling, identified through increased immunoreactivity of osteoblast and osteoclast markers. Tumor cells occasionally grew outside the tibia, and proliferation and apoptotic rates a few days after treatment were evaluated by scoring BrdU- and caspase-3-positive tumor cells inside and outside the bone marrow cavity, separately. Apoptosis was significantly induced outside, but unaffected inside, the tibial bone by either castration or NVP-AEW541, and the maximum increase (2.7-fold) was obtained by the combined treatment. Proliferation was significantly reduced by NVP-AEW541, independently of growth site, although the maximum decrease (24%) was observed when NVP-AEW541 was combined with castration. Tumor cell IGF-1R immunoreactivity was evaluated in clinical PCa bone metastases (n = 61), and positive staining was observed in most cases (74%). In conclusion, IGF-1R inhibition may be evaluated in combination with ADT in patients with metastatic PCa, or in combination with therapies for the subsequent development of castration-resistant disease, although diverse responses could be anticipated depending on metastasis site.Electronic supplementary materialThe online version of this article (doi:10.1007/s10585-017-9848-8) contains supplementary material, which is available to authorized users.

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“…In this regard, studies are indicating that single nucleotide polymorphisms (SNPs) in IGF system related genes modify the activity/function of the IGF system. In addition, there is also evidence that IGF-I splice variants are differentially expressed between non-cancerous and cancerous cells, implying that the expression pattern of the various IGF-I transcripts and the respective proteins may have different functions in cancer biology [199]. Thus, future genome wide studies in MM should focus on the identification of genetic variants of the IGF system as a whole.…”

Section: Lessons Learned From Previous Clinical Trialsmentioning

confidence: 99%

The insulin-like growth factor system in multiple myeloma: diagnostic and therapeutic potential

et al. 2016

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Multiple myeloma (MM) is a highly heterogeneous plasma cell malignancy. The MM cells reside in the bone marrow (BM), where reciprocal interactions with the BM niche foster MM cell survival, proliferation, and drug resistance. As in most cancers, the insulin-like growth factor (IGF) system has been demonstrated to play a key role in the pathogenesis of MM. The IGF system consists of IGF ligands, IGF receptors, IGF binding proteins (IGFBPs), and IGFBP proteases and contributes not only to the survival, proliferation, and homing of MM cells, but also MM-associated angiogenesis and osteolysis. Furthermore, increased IGF-I receptor (IGF-IR) expression on MM cells correlates with a poor prognosis in MM patients. Despite the prominent role of the IGF system in MM, strategies targeting the IGF-IR using blocking antibodies or small molecule inhibitors have failed to translate into the clinic. However, increasing preclinical evidence indicates that IGF-I is also involved in the development of drug resistance against current standard-of-care agents against MM, including proteasome inhibitors, immunomodulatory agents, and corticoids. IGF-IR targeting has been able to overcome or revert this drug resistance in animal models, enhancing the efficacy of standard-of-care agents. This finding has generated renewed interest in the therapeutic potential of IGF-I targeting in MM. The present review provides an update of the impact of the different IGF system components in MM and discusses the diagnostic and therapeutic potentials.

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The insulin-like growth factor (IGF) axis as an anticancer target in prostate cancer

Cited by 47 publications

References 104 publications

PSMA redirects cell survival signaling from the MAPK to the PI3K-AKT pathways to promote the progression of prostate cancer

PSMA redirects cell survival signaling from the MAPK to the PI3K-AKT pathways to promote the progression of prostate cancer

Inhibition of the insulin-like growth factor-1 receptor potentiates acute effects of castration in a rat model for prostate cancer growth in bone

The insulin-like growth factor system in multiple myeloma: diagnostic and therapeutic potential

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