Medicine by Alexandros G. Sfakianakis: Forecasting and Targeting a Rare Cancer with Hypoxia-Inducible Factor

Τρίτη 12 Δεκεμβρίου 2017

Forecasting and Targeting a Rare Cancer with Hypoxia-Inducible Factor

By Jamshed Arslan Pharm.D.

Cancers of nerve, adipose, and other soft tissues are called soft tissue sarcomas (STS). Malignant peripheral nerve sheath tumor (MPNST) is an example of a rare and hard-to-treat STS; even after the surgical removal (which is the only viable option), the tumor often relapses causing poor patient survival. The search for novel treatment targets led a team of researchers in Japan [1] to a transcription factor called hypoxia-inducible factor (HIF). Normally, HIF-1α adapts cells to hypoxic conditions by localizing to the nucleus where it regulates cell growth with the help of transcriptional co-activators p300 and CBP. The team found that increased nuclear HIF-1α indicated poor prognosis in MPNST, and most importantly, inhibiting HIF-1α signaling by a small molecule called chetomin, resulted in apoptosis in MPNST cells. Hence, HIF-1α can serve both as a poor prognostic marker and a therapeutic target in MPNST.

The researchers established the clinical significance of HIF-1α by showing that two thirds of the 82 specimens from MPNST patients were positive for nuclear HIF-1α. Immunohistochemical staining (anti-HIF-1α, anti- HIF-2α, and MIB-1) and hematoxylin and eosin staining revealed that positivity of HIF-1α and MIB-1, but not the HIF-2α, were associated with lower patient survival rates and increased MPNST cell growth. These histological results were validated by expression analysis in MPNST cell lines: nuclear expression of HIF-1α and HIF-1α-downstream genes (VEGFA and GLUT1) were enhanced under hypoxic conditions.

AKT signaling pathway: The AKT/mTOR pathway is activated in MPNST and is associated with increased HIF-1a protein levels [2,3].

To study the effects of reversing HIF-1α expression, small interfering RNAs against HIF-1α were used. The cell growth and viability assays revealed that HIF-1α-suppression reduces MPNST proliferation by decreasing the expression of downstream genes (VEGFA, GLUT1, and BNIP3). The team found that HIF-1α promoted MPNST cell growth in a cell-autonomous manner: nuclear HIF-1α expression was not correlated with microvessel density, indicating that tumor progression does not involve angiogenesis.

Next, the team used a screening kit (SCADS; Screening Committee of Anticancer Drugs, Japan) to find a small molecule that could potentially inhibit HIF-1α in MPNST. Only chetomin, a chemical that disrupts the binding of HIF-1α with p300/CBP complex, was found to dose-dependently reduce growth and induce apoptosis in MPNST cells. Interestingly, western blotting revealed an unaltered nuclear HIF-1α expression, indicating that chetomin inhibits only HIF-1α/p300 interaction, not the HIF-1α gene expression

Previously, studies on the role of HIF-1α in cancers had either focused on solid tumors [4,5] or used heterogenous populations containing bone and soft tissue sarcomas [6]. The research team in Japan overcame these problems by using cell lines and clinical specimens specific to MPNST. The study is also unique in combining clinical and experimental data to support the inhibition of HIF-1α signaling as a feasible strategy against MPNST.

Explore the interactive AKT pathway

Jamshed Arslan, Pharm D.
University of Alabama at Birmingham, School of Medicine
Dr. Arslan studies cell signaling in mitochondrial defects in C. elegans and transgenic mice.

References

Fukushima, Suguru, et al. "Hypoxia-Inducible Factor 1 α is a Poor Prognostic Factor and Potential Therapeutic Target in Malignant Peripheral Nerve Sheath Tumor." PLoS One, vol. 12, no. 5, n. pag. http://ift.tt/2Ac7QgP
Endo M, et al. Prognostic significance of AKT/ mTOR and MAPK pathways and antitumor effect of mTOR inhibitor in NF1-related and sporadic malignant peripheral nerve sheath tumors. Clinical Cancer Research: An Official Journal of the American Association for Cancer Research. 2013; 19(2):450–61. http://ift.tt/2l0x6nw
Masoud, G. N., & Li, W. (2015). HIF-1α pathway: role, regulation and intervention for cancer therapy. Acta Pharmaceutica Sinica. B, 5(5), 378–389. http://ift.tt/2Ac7RkT
Wang, Qian, et al. "Prognosis Value of HIF-1α Expression in Patients with Non-Small Cell Lung Cancer." Gene, vol. 541, no. 2, 2014, pp. 69–74. http://ift.tt/2l0x6Uy
Fan, Yang, et al. "Prognostic Significance of Hypoxia-Inducible Factor Expression in Renal Cell Carcinoma: A PRISMA-compliant Systematic Review and Meta-Analysis." Medicine, vol. 94, no. 38, 2015, p. e1646. http://ift.tt/2AdedRa
Li, Yongjiang, et al. "Prognosis Value of Hypoxia-Inducible Factor-1α Expression in Patients with Bone and Soft Tissue Sarcoma: A Meta-Analysis." SpringerPlus, vol. 5, no. 1, 2016, n. pag. http://ift.tt/2l0wFto