Erin B. Dickerson, PhD, University of Minnesota, D14CA-047


RESULTS: Researchers identify a chemotherapy resistance mechanism in hemangiosarcoma tumor cells
Hemangiosarcoma is a common and deadly tumor of dogs. Growing in areas with a rich blood supply, such as the
spleen or heart, many dogs die suddenly, secondary to massive blood loss when tumors rupture. Hemangiosarcomas
also are quick to spread to other areas of the body, so even when tumors are discovered early, the tumors have
already spread. Prognosis for this cancer hasn’t improved in nearly two decades, and new treatment options are
desperately needed.

Morris Animal Foundation-funded researchers at the University of Minnesota felt that by gaining a better
understanding of the underlying biology of this aggressive tumor, they could discover new ways of improving longterm
prognosis in dogs with hemangiosarcoma. Their targets were cells important in tumor growth, spread and drug
responses.

The research team successfully identified a drug-resistant cell population within hemangiosarcoma tumors that may
be an important player in chemotherapy resistance. The cells identified are extremely efficient at isolating cancer
drugs in compartments called lysosomes. By trapping the drug within lysosomes, cancer cells were able to prevent
the chemotherapy from reaching its target, effectively neutralizing the drug. This new information helps explain why
some hemangiosarcoma tumors become chemotherapy resistant.

The Minnesota team also found that hemangiosarcoma cells with a high surface expression of a protein called
colony-stimulating factor 1 receptor (CSF-1R) were the culprits in this process. The lysosomes in the cells with higher
expression of CSF-1R were trapping the chemotherapy drug, preventing it from reaching its target, the nucleus of the
cancer cells, in sufficient quantities to be effective. The team started searching for a drug that could prevent the
accumulation of chemotherapy in the lysosomes, and found that the common beta blocker propranolol was effective
in competing with the doxorubicin for lysosomal space. The researchers speculate that if the doxorubicin can’t be
taken into the lysosome (essentially because propranolol got there first), it will be free to reach its target.
The next research step is to further investigate propranolol and other beta blockers to see if they will work in
combination with chemotherapy drugs, and then move to testing this new treatment approach in dogs with
hemangiosarcoma.

This study identified a key mechanism in chemotherapy resistance in hemangiosarcoma tumors. Understanding how
cancer cells hijack and block drugs from reaching their targets will help researchers develop more effective
treatments for this difficult-to-treat cancer in dogs.

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