University of Texas at Dallas scientists have demonstrated that the growth rate of the majority of lung cancer cells relates directly to the availability of a crucial oxygen-metabolising molecule.
In a preclinical study, published in Cancer Research, biologist Dr. Li Zhang and her team showed that the expansion of lung tumours in mice slowed when access to haem – the oxygen-binding molecule in haemoglobin – was restricted.
The researchers also showed that those same cancers grew faster when more haem was available than normal.
With an eye toward exploiting the cancer’s haem dependency, two of Zhang’s graduate students in the Department of Biological Sciences then engineered and extensively characterised new molecules aimed at starving the cancer cells of the molecule that allows them to proliferate so quickly.
The findings suggest a potential new path forward in treating non-small cell lung cancer (NSCLC), which comprises about six out of every seven cases of lung cancer, the leading cause of cancer-related death in the U.S.
“I’ve been working on haem for my entire career,” said Zhang, who joined the UT Dallas faculty in 2007. “In 2013 I began working on lung cancer. In that time, our results have convincingly shown the relevance of haem to this disease.”
Zhang, the Cecil H. and Ida Green Distinguished Chair in Systems Biology Science and professor of biological sciences in the School of Natural Sciences and Mathaematics, edited a textbook about haem biology in 2011.
Her previous work established that lung cancer cells consumed oxygen at a faster rate than normal lung cells, indicating haem’s critical role.
The team emphasised that its potential treatment approach is designed to work in tandem with chemotherapy or other forms of cancer remedy, not by itself.
“This method wouldn’t kill tumours; it would delay their growth,” Zhang said. “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.”
Zhang’s new results emphasise that tumours create energy using molecules other than glucose – a type of sugar known since the 1920s to feed tumours.
Where more haem is being made, more oxygen is consumed to make more adenosine triphosphate (ATP) – the energy-carrying molecule that fuels many activities in living cells.
Take the haem away, and cancer cell growth slows down.
“Years ago, it was believed that cancer cells did not use oxygen, only glucose, to make energy,” Zhang said. “Now we know that most cancer cells use oxygen, and this type of lung cancer cell is an example. It oxidises the glucose to generate energy much more efficiently, manufacturing about 30 ATP molecules per glucose molecule.”
Sagar Sohoni and Poorva Ghosh, co-first authors of the study and doctoral students in Zhang’s lab, collaborated to investigate how a series of engineered molecules deny haem to cancer cells.
Zhang said that these haem-sequestering peptides, or HSPs, are able to “hijack” haem from the spaces between cells, where tumours would be able to access it, while leaving alone the haem in healthy cells.
“Haem sequestering doesn’t adversely affect the normal cells,” Zhang said. “They synthesise the little haem they need on their own. Also, our peptide won’t go into cells so it shouldn’t provoke many side effects.”
Demonstrating the reduced progress of haem-starved cancer cells makes a compelling case on its own.
To hammer the point home, Zhang’s team modified NSCLC cells to allow them to obtain haem faster.
Those cells behaved as expected — aggressive and invasive, consuming oxygen quickly and cranking out more ATP.
“Cancer cells’ energy demands are very high compared to the normal cells around them,” Zhang said. “When more haem is available, NSCLC cells grow and reproduce at an alarming rate.”
The next step is to continue refining the design of the HSPs to create a version for use in humans, “further optimising its efficacy while continuing to prove that its toxicity is low,” Zhang said.
“This idea has turned out to be more beautiful than I dreamed of,” she said. “It’s really making sense.”
Source: University of Texas at Dallas