Tumor growth in most lung cancer cells depends on the availability of heme, according to the results of a recent study published in Cancer Research. Of note, heme represents 97% of the body’s functional iron pool, and iron plays a role in tumor formation and progression.
“Targeting heme flux and function offers a potential strategy for developing therapies for lung cancer,” wrote the authors, led by Sagar Sohoni, Department of Molecular and Cell Biology, University of Texas at Dallas, Richardson, TX.
In the current preclinical study, when lung tumors in mice models were limited in access to heme, their growths slowed. Conversely, when lung tumors in mice models were exposed to higher levels of heme than normal, the tumors grew faster.
Sohoni et al found that levels of heme synthesis and uptake, mitochondrial heme, oxygen-utilizing hemoproteins, oxygen consumption, ATP generation, and key mitochondrial biogenesis regulators were heightened in non-small cell lung cancer (NSCLC) cells vs those of non-tumorigenic cells. Additionally, proteins and enzymes associated with heme and mitochondrial functions were upregulated in human NSCLC tissues vs those of normal tissues.
Heme-sequestering peptides (HSP) decreased heme uptake, intracellular heme levels, and tumorigenic functions of NSCLC cells. Whereas, heme supplementation mostly reversed the effect of HSP on cancer functions. Additionally, HSP2 stymied the growth of human NSCLC xenograft tumors in mice. HSP2-treated tumors demonstrated decreased oxygen consumption rates, and lowered ATP levels
The investigators developed NSCLC cell lines with increased heme synthesis or uptake via overexpressing either the rate-limiting heme synthesis enzyme ALAS1 or uptake protein SLC48A1 in order to verify the importance of heme in boosting tumorigenicity. These generated cells demonstrated enhanced migration and invasion, and accelerated tumor growth in mice. Tumors derived from cells with increased heme synthesis or uptake also demonstrated elevated oxygen consumption rates and ATP levels.
Ultimately, these data indicate that elevated heme flux and function form the basis of enhanced mitochondrial oxidative phosphorylation and tumorigenicity in NSCLC cells.
“Elevated heme availability due to increased heme synthesis and uptake causes intensified oxygen consumption and ATP generation, promoting tumorigenic functions and tumor growth in NSCLC,” stressed the authors.
Alternative therapeutic approaches are needed in the treatment of lung cancer, which is the top cause of cancer-related death in the United States. Although several chemotherapeutic and targeted therapeutic agents exist to treat lung cancer, the 5-year survival rate of 18% hasn’t budged. Multiple driver genes and intra-tumoral genetic heterogeneity decreases the efficacy of targeted therapies. In particular, PD-1/PD-L1 checkpoint inhibitors—including nivolumab, pembrolizumab, and atezolizumab—only extend median overall survival by about 3 months as second-line treatment of advanced NSCLC vs docetaxel alone.
With front-line therapy, the median progression-free survival lengthens from 6.0 months with platinum-doublet chemotherapy to 10.3 months with pembrolizumab in patients with untreated NSCLC and high levels of PD-L1 expression.
Exploiting heme “wouldn’t kill tumors; it would delay their growth,” concluded principal investigator Li Zhang. “So it would not be a stand-alone treatment, but it could replace less effective forms of therapy that rely on inhibition of angiogenesis — the creation of new blood vessels.”