Misfolded proteins in liver cells contribute to the development of liver cancer

The study, led by Dr.
Randal J.
Kaufman, found that misfolded proteins in liver cells contribute to the development of liver cancer, shedding new light on
the mysterious origins of one of the world's deadliest diseases.
The findings, published in the journal Molecular Therapeutics, also help improve the safety of
certain hemophilia gene therapies.

"It takes many years for liver cancer to develop, but it is one of the fastest-growing causes of cancer-related deaths in the United States," Kaufman said, "There are still many mysteries about what causes liver cancer, and our results show for the first time that misfolded proteins in liver cells play a key role
.
" This effect
needs to be taken into account when developing treatments that help the liver produce protein, such as those for hemophilia A.
”

About 400 babies are born each year with hemophilia A, a bleeding disorder
caused by a deficiency in a clotting protein called factor VIII (FVIII).
Hemophilia B has similar symptoms, but is rarer, and is caused
by a deficiency of a different protein.
Both diseases can be fatal
if left untreated.

"Years ago, the only way to treat hemophilia was a protein isolated from human blood, which was a big risk for patients, thankfully this is no longer the case, but we still have a long way to go to make the treatment of this disease safe, effective and economical
for everyone.
"

Factor VIII is usually manufactured
by liver endothelial cells.
Protein replacement therapy, currently the standard treatment for hemophilia A, works by injecting patients with FVIII
produced by lab-grown mammalian cells.
While this method is effective, it is also expensive and inefficient
.
What's more, this approach does not cure the disease, and patients must continue to receive treatment
throughout their lives.

Gene therapy avoids some of the drawbacks
of standard hemophilia treatment by helping liver cells, the main cell type of the liver, make their own clotting proteins.
This approach is currently undergoing clinical trial studies and has recently been approved by the FDA for hemophilia B
.
Gene therapy for hemophilia A isn't far off either, which received conditional approval
from the European Union earlier this year.

However, gene therapy hemophilia A has one major drawback: the version of FVIII produced by gene therapy often fails to fold into the correct shape, making it both useless and dangerous
.

Kaufman said: "When misfolded proteins accumulate, it puts a lot of stress on the cells, which is at the heart of
many diseases, including cancer.
" "Gene therapy for hemophilia can change the way we care for people with this disease, but the effects of protein misfolding on liver cells need to be considered to ensure the safety and longevity
of these treatments.
"

To understand whether misfolding of FVIII in liver cells can trigger liver cancer, the researchers helped two groups of mice produce versions of FVIII that were misfolded at different rates
.
The mice were also fed a high-fat diet to accelerate the development of
liver tumors.
This is important because chronic liver stress is often a precursor
to liver cancer.

At the end of the study, all mice with more misfolded proteins developed liver cancer, while only 58 percent of mice in the other group developed liver cancer
.

"We found a direct link
between FVIII misfolding and liver cancer development.
"

The findings suggest that gene therapy for hemophilia may increase the risk
of liver cancer in some patients after years of treatment.
They also suggest that this risk
can be reduced by closely monitoring patients receiving these treatments and developing better-folded FVIII variants that can be used in gene therapy applications.

Dr.
Glenn Pierce, MD, who works at the World Federation of Hemophilia and the National Hemophilia Foundation, said: "This study has potentially far-reaching universal implications
in addition to gene therapy for hemophilia.
" He also co-authored a review
of Kaufman's research in the same edition of Molecular Therapy.
"The findings suggest that the expression of proteins in the liver is misfolded, causing cellular stress, and then a second damage to the liver, such as a high-fat diet, may lead to malignant tumors
.
"

This study was supported by grants from the National Institutes of Health (CA198103, DK113171, P30DK120515, P01HL160472, and T32DK007494).

Journal Reference:

1. Audrey Kapelanski-Lamoureux, Zhouji Chen, Zu-Hua Gao, Ruishu Deng, Anthoula Lazaris, Cynthia Lebeaupin, Lisa Giles, Jyoti Malhotra, Jing Yong, Chenhui Zou, Ype P.
   de Jong, Peter Metrakos, Roland W.
   Herzog, Randal J.
   Kaufman.
   Ectopic clotting factor VIII expression and misfolding in hepatocytes as a cause for hepatocellular carcinoma.
   Molecular Therapy, 2022; 30 (12): 3542 DOI: 10.
   1016/j.
   ymthe.
   2022.
   10.
   004