Molecular Cell breaks down one of the deadliest cancers: how liver cells go astray

Liver cancer is one of
the deadliest cancers.
A team of researchers from the University of Basel has now discovered how healthy liver cells turn into tumour cells
.
Comprehensive metabolic changes transform mature hepatocytes into immature progenitor cells
.
These cells proliferate rapidly, forming tumors
.


The causes of liver cancer are diverse
.
In the Western world, in addition to the metabolic disorders associated with obesity, the main causes are hepatitis C virus infection and heavy alcohol consumption
.
Although hepatocellular carcinoma is relatively rare compared to other types of cancer, it is one of the leading causes of
cancer-related death due to poor prognosis.

Like all tumor cells, liver cancer cells proliferate rapidly and uncontrollably
.
This requires a fundamental change
in their metabolism.
In the scientific journal Molecular Cell, researchers led by Professor Michael N.
Hall of the University of Basel's Center for Biology report that liver cancer cells reduce the production
of a central metabolic molecule.
In this way, the overall metabolism is rewired, allowing tumor cells to grow faster
.

The liver is the largest metabolic organ in the human body
.
It processes and stores nutrients and detoxifies harmful compounds
.
When a healthy liver cell becomes cancerous, it loses its function
.
"Tumor cells are selfish
.
They change metabolism to grow as fast as possible," explains
cancer researcher Dr.
Dirk Mosman.
"At the same time, however, they stopped their function
as liver cells.
This is why liver function is impaired in patients with hepatocellular carcinoma
.
”

Major changes in cellular metabolism

The acetyl-CoA molecule plays a central role
in cellular metabolism.
On the one hand, it is the end product of many degradation pathways; On the other hand, it requires the production or chemical modification of a large number of other molecules
.
"We found that all acetyl-CoA biosynthetic pathways are downregulated in hepatoma cells," explains first author Dr
.
Sujin Park.
"This leads to a decrease in acetyl-CoA, which in turn affects many other proteins, including metabolic enzymes
.
" The function of these enzymes is altered because they are no longer modified
by acetyl-CoA.
This can help tumor cells, for example, convert sugar into energy
more efficiently.
”

Another effect is that acetyl-CoA affects cell differentiation
.
Decreased acetyl-CoA levels promote hepatocyte dedifferentiation
.
In other words, they are reprogrammed to an early, immature stage of development
.
They lose their characteristic function and begin to split
rapidly.
Mossmann said: "We wanted to know why all acetyl-CoA metabolic pathways are inhibited in tumor cells
.
" "We found the answer in two proteins, so-called transcription factors that regulate a broad gene profile that triggers metabolic changes
extensively.
"

Cancer with special characteristics

The researchers observed this mechanism
in both mouse and patient liver tumors.
The patient's tumor samples were taken from Professor
Markus Heim from the Department of Biomedical Sciences of the University of Basel and the University Hospital Basel.
"These two transcription factors are actually key players — inhibiting them in mice can prevent tumors
," Parker said.
"In addition, metabolic changes in tumor cells show a 'signature' that can also be found in other types of cancer, such as prostate cancer and pancreatic cancer
.
"

Metabolic cancer signaling also provides information about
disease progression.
It is associated with
low survival rates.
One of the biggest problems is that liver cancer is asymptomatic for a long time, so the disease is usually detected
at an advanced stage, late stages.
Surgery or liver transplantation is usually no longer an option
.
So, an interesting question is when this cancer trait was formed, and whether it can be used as a biomarker for liver cancer screening and early diagnosis
.