Removing Cancer Cell Debris Improves Conventional Cancer Treatments

Cancer therapies are designed to kill tumor cells, but produce tumor cell debris in the process. In a study published in The Journal of Experimental Medicine, researchers from Brigham and Women’s Hospital and colleagues show that leftover debris can stimulate inflammation and tumor growth, but that molecules called resolvins can block that unwanted inflammatory response. The findings point towards a new way to enhance the effectiveness of current cancer therapies and potentially prevent tumor recurrence.

When conventional cancer treatments, such as radiation or chemotherapy drugs, break apart tumors, they can also spread and stimulate the production of proinflammatory cytokines. These signaling molecules, known to promote tumor growth, were at the center of the investigation.

“Dead and dying tumor cells are an underappreciated component of the tumor microenvironment that may promote tumor progression,” said Professor Charles Serhan, PhD, DSc, Department of Anesthesiology, Perioperative and Pain Medicine at BWH.

The team administered a variety of therapeutic drugs to lab-cultured cancer cells and collected the resulting debris. When co-injected into mice with a small number of non-growing cancer cells, the debris stimulated tumor formation. A similar test treated mice with the chemotherapy drugs such as cisplatin and vincristine to generate debris in vivo, supporting the conclusion that the debris helped surviving cancer cells form tumors. The researchers concluded that a lipid called phosphatidylserine stimulated immune cells to produce a “cytokine storm” when exposed to the cancerous cells and caused the growth.

The researchers reasoned that if drug-generated debris was promoting tumor growth, clearing the debris might stop it. The team focused on the body’s own resolvins which act as stop signals to end or “resolve” the inflammation. Resolvins counter the debris-stimulated proinflammatory cytokines and stimulate the immune system including white blood cells called macrophages (“the big eaters”) to remove or “mop up” the debris.  Resolvins are biosynthesized by the body from omega-3 essential fatty acids. Resolvins were discovered at the Brigham and Women’s Hospital by Dr. Serhan and his laboratory and are a new approach to turn off inflammation in the human body to prevent a “cytokine storm” rather than blocking a single pro-inflammatory factor

Treating mice with small amounts of resolvins inhibited the subsequent therapy-stimulated tumor growth and prevented cancer cells from spreading. Resolvin treatment enhanced the activity of several cytotoxic therapies against a variety of tumor types resulting in tumor regression. Clinical developments using resolvins as potential therapeutic approaches are already in progress for several inflammatory and neurodegenerative diseases.

“Stimulating the clearance of tumor cell debris via specialized pro-resolving mediators represents a new approach to prevent tumor growth and recurrence,” the authors write.

This work was supported by the National Cancer Institute grants RO1 01CA170549-02 and GM095467; the Stop and Shop Pediatric Brain Tumor Fund; the CJ Buckley Pediatric Brain Tumor Fund; Alex Lemonade Stand; Molly’s Magic Wand for Pediatric Brain Tumors; the Markoff Foundation Art-In-Giving Foundation; the Kamen Foundation; Jared Branfman Sunflowers for Life; and The Wellcome Trust program 086867/Z/08.

Paper Cited: Sulciner, M et al.Resolvins suppress tumor growth and enhance cancer therapy” The Journal of Experimental Medicine DOI: 10.1084/jem.20170681

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Weight Loss and Risk of Death: Rheumatoid Arthritis Findings May Have Wider Implications

Researchers call it the obesity paradox: the phenomenon, observed in studies of patients with rheumatoid arthritis (RA) and other chronic conditions, where patients who are obese have a lower risk of death than those who weigh less. But most of these studies focused on patients who have RA for many years, and involved relatively little follow-up prior to death. Researchers from Brigham and Women’s Hospital evaluated the effect of RA diagnosis on weight change and how this subsequently affects mortality risk. They did this by comparing women from the Nurses’ Health Study who had been diagnosed with RA to a similar group of women who had not been diagnosed with RA. Their results suggest that the findings from previous studies regarding lower weight being associated with higher mortality may not be directly related to RA and instead reflect a more generalized phenomenon. Their study is published this week in Arthritis & Rheumatology.

“Our findings are important because they show that weight gain does not offer a mortality benefit for patients with RA,” said Jeffrey Sparks. “Our observations indicate that clinicians can encourage healthy weight loss strategies for RA patients.”

Prior studies testing the relationship between RA and weight loss have typically been performed by including only patients with RA, making it unclear whether the patterns reported were specific to RA or related to general population that was frail and of advanced age. In the current study, the research team narrowed in on the early RA period around the time when women were diagnosed with RA, two to four years after diagnosis or a similar period for women who were comparators. In both RA and the comparator groups, those who had severe weight loss (30 pounds or more) had the highest risk of death decades later. This increased mortality risk for severe weight loss was most likely related to unintentional weight loss, rather than healthy weight loss. Weight gain in this early RA or index period had no effect on mortality risk for either the RA or comparator groups.

“There has been a question among clinicians of whether obesity might offer a mortality benefit for patients with RA, but our data suggest that weight gain was not protective. Instead, we wonder whether people who gain or maintain weight have better observed mortality rates because they aren’t sick, unlike those who unintentionally lose weight,” said Sparks.

The research team accounted for certain factors – such as physical activity and diet – that might contribute to weight loss, but in the future, would like to understand the mechanisms for how weight change may influence risk of death.

This work was supported by the Rheumatology Research Foundation Disease-Targeted Innovative Award, Scientist Development Awards, the National Institutes of Health (grant numbers K24 AR052403, P60 AR047782, L30 AR066953, L30 AR070514, R01 AR049880, UM1 CA186107, K23 AR069688, K01 AR064351, and T32 AR007530). The funders had no role in study design, data collection, analysis, decision to publish, or preparation of the manuscript. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Paper cited: Sparks JA et al. “Weight change in the early rheumatoid arthritis period and risk for subsequent mortality among women with RA and matched comparators” Arthritis & Rheumatology DOI:10.1002/art.40346

Researchers from Brigham and Women’s Hospital led by Ying Bao, MD, ScD, an epidemiologist in BWH’s Channing Division of Network Medicine and Assistant Professor at Harvard Medical School, have found that women with stronger social networks had better survival after colorectal cancer diagnosis and conclude that social network strengthening could be a tool for management of colorectal cancer.

Colorectal cancer is the third most commonly diagnosed and second leading cause of cancer death in the United States. At current rates, approximately 5 percent of individuals will develop a cancer of the colon or rectum within their lifetime. Though social network research has been done in other diseased populations, very few studies have examined the association between social network and survival in varying cancer sites.

The team utilized data from 896 women who participated in the Nurses’ Health Study and had been diagnosed with colorectal cancer between 1992 and 2012. Social integration was assessed every four years during that time using the Berkman-Syme Social Networks Index; the value scale accounts for factors like marital status, social network size, contact frequency and religious or social group participation. This helped organize a patient rating system that identified patients on a range from socially isolated to socially integrated.

The findings indicated that, overall, women with high levels of social integration before a colorectal cancer diagnosis had significantly reduced risk of all-cause and colorectal cancer-specific mortality, particularly among older women. Though the number of extended ties (religious or social group participation) weren’t associated with survival, the presence of more intimate ties (family and friends) was associated with a significantly lower death rate.

“When a patient is diagnosed, health care providers can look to the patient’s social network to see if it provides necessary resources or whether outside help might be something to consider,” said Bao who is also an assistant professor at Harvard Medical School. “That could be assistance from social workers, for example, to ensure access to care. For physicians, portions of a care plan aimed at strengthening a patient’s social network can be valuable tools that haven’t always been considered in the past.”

Due to the complexity of network interactions, there are many pathways through which social networks could cause improved survival among cancer patients. Some prior research indicates that higher levels of social integration are associated with lower levels of inflammation and thus disease progression; other studies indicate it relates to a reduction in psychological stress and poor health behaviors that may contribute to cancer progression. Support from social networks, such as assistance in getting to medical appointments, reminders to take medications, and help with nutrition and mobility, may also explain the observed association. Future investigations are required to understand how these factors are influencing different kinds of patients and their care plans.

The Nurses’ Health Study is supported by NIH grants UM1CA186107 and P01CA87969. Dr. Bao is supported by NIH grants KL2TR001100 and P30DK046200, and by Department of Defense grant CA150357. Dr. Fuchs is supported by NIH grants P30CA016359, R01CA169141, R01CA118553, and by Stand-Up-to-Cancer.

Paper Cited: Sarma, E et al. “Social Integration and Survival after Colorectal Cancer Diagnosis” Cancer DOI: 10.1002/cncr.31117