A team of investigators, lead by scientists at the Bellvitge Biomedical Research Institute (IDIBELL) in Barcelona, has just released new findings from a study on how tumor cells respond to a lack of nutrients. Knowing that some solid tumors have a very high growth rate, which often leads to a lack of vascularization due to the impossibility to develop the blood vessels that accompany and nourish it, the research team observed that cells respond by releasing cytokines and chemokines, molecules that attract the first defenses of the immune system, which ultimately inhibit a more specific and effective attack.

Findings from the new study—published recently in PNAS through an article entitled “Starvation and antimetabolic therapy promote cytokine release and recruitment of immune cells”— also show that the released cytokines will promote the formation of new blood vessels that nourish the tumor again.

“Poorly irrigated tumors exhaust nutrients from their environment,” the authors noted. “On the other hand, innate immune cells, such as neutrophils and macrophages, have been frequently shown to infiltrate tumors and promote an immunosuppressive environment.”

Reduced nutrient levels in the less vascularized parts of the tumor are known to trigger stress responses. As senior study investigator and senior scientist at IDIBELL Cristina Muñoz-Pinedo, PhD, points out, “the stress response due to lack of nutrients, known as an integrated stress response, induces the cell production of alarm proteins. And those proteins are closely related to cancer progression”. This article demonstrates that this response participates in the secretion of inflammatory cytokines in many types of tumor cells in culture, from lung cancer cells to cervical cancer or rhabdomyosarcoma.

Previous studies of other groups point out that the inflammation that takes place in tumors could prevent an effective immune response to attack tumor cells. Tumors in mild and constant inflammation state present elevated levels of the cytokines and chemokines found in this study. For this reason, the authors hypothesize that this inflammation could be caused by the lack of nutrients that cells detect and interpret as a wound or infection.

The authors hypothesized that, under these circumstances, the tumor cells could be acting as a non-healed wound. When we have a wound, blood flow is interrupted at some point in our body, and this lack of blood flow could be the signal that triggers the wound healing response: the attraction of the first defenses of the immune system and the generation of new blood vessels, in other words, the inflammatory response. This response could be reproduced in solid tumors, in which the lack of blood supply is interpreted as a wound, but for the moment we can only consider this an idea not yet proven.

The signals sent by tumor cells not only impede the attack of the immune system but also induce the modification of the tissue that accompanies them. Specifically, this work shows that, when tumor cells are glucose deprived, they initiate a signal cascade to promote angiogenesis in vitro, that is, the creation of new blood vessels that return the blood flow and the nutrients.

“We analyzed secretomes from glucose-deprived cells, which revealed up-regulation of multiple cytokines and chemokines, including IL-6 and IL-8, in response to starvation stress,” the authors wrote. “Starvation-induced cytokines were cell type-dependent, and they were also released from primary epithelial cells. Most cytokines were up-regulated in a manner dependent on NF-κB and the transcription factor of the integrated stress response ATF4, which bound directly to the IL-8 promoter. Furthermore, glutamine deprivation, as well as the antimetabolic drugs 2-deoxyglucose and metformin, also promoted the release of IL-6 and IL-8.”

There is a type of drug that attacks tumors called antimetabolic drugs. They act by impairing nutrient processing of tumor cells, and thus, through starvation, promote the death of tumor cells. These drugs, despite having good results in animal models, often fail in clinical trials with patients.

The results of this study could explain the lack of efficacy of this type of drugs since this work describes that two antimetabolic drugs also cause tumor cells to secrete cytokines and chemokines. These drugs could be causing an inflammatory response due to a lack of nutrients, which could promote tumor survival.

“Our results show that, when nutrients are low, tumor cells secrete factors related to wound healing that stimulates endothelial cells and attracts innate immune cells,” the authors concluded. “This suggests that targeting signals elicited by metabolic stress may help the immune system target malignant cells and that metabolites regulate the communication between immune and tumor cells also through modulation of peptidic signals.”

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