Liver cancer metabolism offers a new therapeutic strategy
Hepatocellular carcinoma (HCC) alters its metabolism in a way that makes it susceptible to disruptions in the supply of a key molecule, arginine. Researchers from the Perelman School of Medicine at the University of Pennsylvania developed an approach in mice that left HCC tumors in a senescent state.
Their results are published in the journal Cellular metabolism.
“HCC is a generally fatal malignancy with genetic heterogeneity and limited therapeutic responses,” the researchers wrote. “Here we demonstrate that HCCs consistently repress urea cycle gene expression and thus become auxotrophic for exogenous arginine. Surprisingly, arginine import depends solely on the cationic amino acid transporter SLC7A1, the inhibition of which slows the growth of HCC cells in vitro and in vivo.
“Essentially, we have identified a metabolic property of most liver cancers that offers the possibility of effectively treating these cancers, using drugs already approved or in development,” said study lead author Celeste Simon. PhD, Arthur H. Rubenstein, MBBCh Professor in the Department of Cell and Developmental Biology and Scientific Director of the Abramson Family Cancer Research Institute at Penn Medicine.
The approach taken by Simon and his team – targeting tumor metabolism – is one that cancer researchers have increasingly explored in recent years.
Researchers first established from existing databases of cancer cell gene activity and from testing of patient tumor samples and cancer cell lines that virtually all HCCs speed up their metabolism. by suppressing a biochemical process called the urea cycle. The urea cycle normally produces, among other things, an amino acid called arginine, which is a building block of proteins and has many other important functions. The researchers showed that HCC cells compensate for their loss of internal arginine production in the urea cycle by importing arginine from their environment, mainly via a transporter protein called SLC7A1.
Blocking SLC7A1 activity in HCC cells to deprive them of arginine did not kill the HCC cells. Instead, arginine deprivation triggered a stress response that threw the cells into a slow, dormant growth mode from which they could recover if arginine became available again. The researchers then tried to block the stress response as well and found that the HCC cells were now forced into a deeper and more difficult to reverse state of non-growth called senescence.
The results point to the possibility of a three-part combination treatment – to starve HCC tumors of arginine, to block the ensuing stress response and induce senescence, and, finally, to kill the resulting senescent HCC cells and stop tumor growth.
“It is conceivable that this type of combination treatment, if implemented correctly, would also make many patients more responsive to other treatments such as immunotherapies,” Simon said.