Journal Club

Highlighting recently published papers selected by Academy members

Suffocating cancers that thrive without oxygen

New findings on the protein CDCP1 provide a link between the low oxygen environments of some tumors, and their ability to spread between sites in the body. Despite the fact that many cancer cells thrive without oxygen, understanding the molecular pathways involved gives researchers a chance to suffocate these tumors for good.

Most cells in the human body can’t survive for long without oxygen—the element we gulp in with every breath is vital to building molecules, carrying out chemical reactions, and storing energy. But cancerous cells aren’t like other cells in the body. Many tumors, in fact, thrive under conditions of low oxygen, called hypoxia. And tumors depleted of oxygen have been found, time and time again, to be more dangerous, faster growing, faster spreading, and more resistant to treatments than other tumors. Why? Cells have built in programs that put them into crisis mode when oxygen levels in their neighborhood drop; altering their metabolism to make it more efficient, turning off cell death pathways in a desperate attempt to survive, and spurring the growth of new blood vessels toward the area. This hypoxia-induced ultra-survival program is just what tumor cells need to help them evade death and grow uncontrollably.

The new PNAS Early Edition paper by Emerling et. al. serves as a reminder that many unexpected cancer-linked genes may tie back to this hypoxia program in tumor cells. It also brings the results back to real patients, suggesting a potential new drug target for those with oxygen-depleted cancers.

Emerling et. al. were studying the response of tumor cells to hypoxia when they noticed that whenever the amount of oxygen dropped, levels of the protein CDCP1 increased. CDCP1 had never before been linked to oxygen, but in a 2011 PNAS paper by Liu et. al., CDCP1 had been connected to the ability of melanomas to spread throughout the body. More CDCP1 meant a higher chance of the melanoma spreading to the lung, for example. Until now, however, scientists didn’t have a good idea of why this was true, or why different cancers had different levels of CDCP1.

The team of researchers involved in the new paper—mostly based at Harvard Medical School and its associated hospitals—began testing the link between CDCP1 and oxygen to see if it could explain the protein’s role in helping cancers spread. Usually, cancer cells cut off from oxygen are more likely to migrate away from the tumor, the first step in spreading to distant organs. But when Emerling et. al. shut off CDCP1 in a group of cancer cells, low oxygen levels no longer increased the cells’ ability to migrate away—the protein acted as an off-switch against the cancer spreading. CDCP1, the results suggest, could be a missing link between hypoxia and tumor metastasis.

Renal cell carcinoma patients with high levels of CDCP1 in their tumors survived, on average, shorter after their date of diagnosis than those with low levels of CDCP1 in their tumors.

Renal cell carcinoma patients with high levels of CDCP1 in their tumors survived, on average, shorter after their date of diagnosis than those with low levels of CDCP1 in their tumors.

The scientists went on to test levels of CDCP1 in cell lines from real human tumors. Whenever a cancer had high levels of HIF-2α (hypoxia-inducible factor-2α), a protein that cells produce in response to low oxygen, it also had high levels of CDCP1, helping solidify the connection between hypoxia and CDCP1. Bladder, breast, colorectal, kidney, ovarian, and pancreatic tumors showed particularly high levels of CDCP1, they found. Moreover, when the team analyzed the patient data corresponding to the tumor samples, they discovered that those with higher levels of CDCP1 had decreased survival times and an increased chance of the cancer spreading.

The results hint that CDCP1 could be an attractive drug target to block the spread of tumors stemming from hypoxic environments.  This could be particularly applicable to cases of clear cell renal cell carcinoma (ccRCC)—in many of these kidney cancers, a master oxygen-sensing protein is mutated, and hypoxia programs are constantly activated, whatever levels of oxygen the tumor is exposed to. Thirty percent of patients with ccRCC are diagnosed with metastatic tumors, and the cancer is notoriously hard to treat with chemotherapy. Shutting down CDCP1 might be one way to make these cancers less likely to spread, and more susceptible to treatments—it will take more work, though, to know for sure whether this approach has merit.

Categories: Medical Sciences
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