Study reveals cancer therapy's double-edged sword... and how to blunt it

November 30, 2017, Rockefeller University Press
Resolvin treatment (right) increases the uptake of tumor cell debris (green) into macrophages (red) and suppresses the production of proinflammatory cytokines, thereby preventing the remains of dead and dying tumor cells from stimulating tumor growth. Credit: Sulciner et al., 2018

Researchers from Harvard Medical School and the Institute of Systems Biology have discovered that the remains of tumor cells killed by chemotherapy or other cancer treatments can actually stimulate tumor growth by inducing an inflammatory reaction. The study, which will be published November 30 in The Journal of Experimental Medicine, also reveals that a family of molecules called resolvins can suppress this unwanted inflammatory response, suggesting new ways to enhance the effectiveness of existing cancer therapies.

Conventional, radiation- and drug-based cancer therapies aim to kill as many tumor cells as possible, but the debris left behind by dead and dying cancer cells can stimulate the production of proinflammatory cytokines, signaling molecules that are known to promote tumor growth. "Dead and dying tumor cells are an underappreciated component of the that may promote ," explains Prof. Charles N. Serhan from Brigham and Women's Hospital, Harvard Medical School.

Serhan and colleagues therefore decided to investigate whether tumor cell debris can stimulate tumor growth. In addition to Serhan, the research team was led by Mark Kieran from the Dana-Farber Cancer Institute and Boston Children's Hospital, Harvard Medical School, Sui Huang from the Institute of Systems Biology in Seattle, and Dipak Panigrahy from the Beth Israel Deaconess Medical Center, Harvard Medical School. Megan Sulciner is the paper's lead author along with co-lead authors Molly Gilligan and Dayna Mudge.

Sulciner et al. began by killing laboratory-cultured cancer cells with a variety of cytotoxic or targeted drugs and found that the resulting debris stimulated when co-injected into mice with a small number of living cancer cells unable to initiate tumor growth on their own. Similarly, treating mice with the chemotherapy drugs cisplatin and vincristine generated tumor cell debris in vivo that enhanced the ability of surviving cancer cells to form tumors.

"Cytotoxic cancer treatment designed to kill tumor cells may be a double-edged sword that directly contributes to tumor progression and relapse because tumor cell debris stimulates the survival and growth of living ," Panigrahy says.

The researchers discovered that tumor cell debris promotes tumor growth because a lipid called phosphatidylserine, which is exposed on the surface of dead and dying cells, stimulates the production of proinflammatory cytokines by immune known as macrophages.

"We reasoned that if drug-generated debris promotes tumor growth, clearance of debris may mitigate this effect," explains Kieran. "Resolvins are a family of endogenous lipid-derived mediators that stimulate the resolution of inflammation by countering proinflammatory cytokines and increasing the uptake of cell debris into macrophages."

Treating mice with small amounts of resolvins inhibited debris-stimulated tumor growth and prevented from metastasizing. Moreover, resolvin treatment enhanced the activity of various cytotoxic therapies against several different types of tumors.

Resolvins are already in clinical development as potential therapeutic approaches for several inflammatory and neurodegenerative diseases. "Targeting the resolvin pathways provides an entirely new, non-toxic, and non-immunosuppressive approach to by increasing the body's natural production of endogenous pro-resolving and antiinflammatory mediators," says Huang.

"While generation of cell debris throughout treatment may explain an inherent therapeutic limit to conventional cancer therapies, stimulating the clearance of such debris via specialized pro-resolving mediators, such as resolvins, represents a novel approach to preventing and recurrence," Serhan adds.

Explore further: Cell death linked to tumor growth in prostate cancer patients

More information: Sulciner et al., 2018. J. Exp. Med. DOI: 10.1084/jem.20170681

Related Stories

Cell death linked to tumor growth in prostate cancer patients

November 27, 2017
The goal of any cancer treatment is to kill tumor cells. Yet, one little understood paradox of certain cancers is that the body's natural process for removing dead and dying cells can actually fuel tumor growth.

Combination immunotherapy targets cancer resistance

November 22, 2017
Cancer immunotherapy drugs have had notable but limited success because in many cases, tumors develop resistance to treatment. But researchers at Yale and Stanford have identified an experimental antibody that overcomes this ...

Uncovering the mechanisms that support the spread of ovarian cancer

October 10, 2016
A very high mortality rate is associated with ovarian cancer, in part due to difficulties in detecting and diagnosing the disease at early stages before tumors have spread, or metastasized, to other locations in the body.

New study offers novel treatment strategy for patients with colon cancer

September 20, 2017
Colorectal cancer is the fourth leading cause of cancer-related deaths worldwide.

Identification of PTPRZ as a drug target for cancer stem cells in glioblastoma

July 19, 2017
Glioblastoma is a malignant brain tumor with high mortality. Cancer stem cells are thought to be crucial for tumor initiation and its recurrence after standard therapy with radiation and temozolomide (TMZ) chemotherapy. Protein ...

Researchers describe how tumors recruit and use stem cells to support tumor growth and progression

October 20, 2016
A new study has identified a mechanism used by tumors to recruit stem cells from bone and convert them into cancer-associated fibroblasts (CAFs) that facilitate tumor progression. This work, which pinpoints the specific biochemical ...

Recommended for you

Targeting molecules called miR-200s and ADAR2 could prevent tumor metastasis in patients with colorectal cancer

April 24, 2018
Colorectal cancer is the third most common cancer worldwide and the third-leading cause of cancer-related deaths. The main cause of death in patients with colorectal cancer is liver metastasis, with nearly 70% of patients ...

Changes in breast tissue increase cancer risk for older women

April 24, 2018
Researchers in Norway, Switzerland, and the United States have identified age-related differences in breast tissue that contribute to older women's increased risk of developing breast cancer. The findings, published April ...

Removing the enablers: Reducing number of tumor-supporting cells to fight neuroblastoma

April 24, 2018
Investigators at the Children's Center for Cancer and Blood Diseases at Children's Hospital Los Angeles provide preclinical evidence that the presence of tumor-associated macrophages—a type of immune cell—can negatively ...

Technology used to map Mars now measuring effect of treatment on tumours

April 24, 2018
A machine learning approach for assessing images of the craters and dunes of Mars, which was developed at The University of Manchester, has now been adapted to help scientists measure the effects of treatments on tumours.

New test could tell doctors whether patients will respond to chemotherapy

April 24, 2018
Less than half the patients diagnosed with cancer respond favorably to chemotherapy, but a new method for testing how patients will respond to various drugs could pave the way for more personalized treatment.

Vitamin A derivative selectively kills liver cancer stem cells

April 23, 2018
Acyclic retinoid, an artificial compound derived from vitamin A, has been found to prevent the recurrence of hepatocellular carcinoma (HCC), the most common form of liver cancer. Now, in research published in Proceedings ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.