Tumor Microenvironment Autophagic Processes and Cachexia: The Missing Link?

Abstract

Cachexia is a syndrome that affects the entire organism and presents a variable plethora of symptoms in patients, always associated with continuous and involuntary degradation of skeletal muscle mass and function loss. In cancer, this syndrome occurs in 50% of all patients, while prevalence increases to 80% as the disease worsens, reducing quality of life, treatment tolerance, therapeutic response, and survival. Both chronic systemic inflammation and immunosuppression, paradoxically, correspond to important features in cachexia patients. Systemic inflammation in cachexia is fueled by the interaction between tumor and peripheral tissues with significant involvement of infiltrating immune cells, both in the peripheral tissues and in the tumor itself. Autophagy, as a process of regulating cellular metabolism and homeostasis, can interfere with the metabolic profile in the tumor microenvironment. Under a scenario of balanced autophagy in the tumor microenvironment, the infiltrating immune cells control cytokine production and secretion. On the other hand, when autophagy is unbalanced or dysfunctional within the tumor microenvironment, there is an impairment in the regulation of immune cell’s inflammatory phenotype. The inflammatory phenotype upregulates metabolic consumption and cytokine production, not only in the tumor microenvironment but also in other tissues and organs of the host. We propose that cachexia-related chronic inflammation can be, at least, partly associated with the failure of autophagic processes in tumor cells. Autophagy endangers tumor cell viability by producing immunogenic tumor antigens, thus eliciting the immune response necessary to counteract tumor progression, while preventing the establishment of inflammation, a hallmark of cachexia. Comprehensive understanding of this complex functional dichotomy may enhance cancer treatment response and prevent/mitigate cancer cachexia. This review summarizes the recent available literature regarding the role of autophagy within the tumor microenvironment and the consequences eliciting the development of cancer cachexia.

Application Route and Immune Status of the Host Determine Safety and Oncolytic Activity of Oncolytic Coxsackievirus B3 Variant PD-H

“…Thus, our data support previous studies with adenoviruses and vaccinia viruses showing that OV can prevent the development of cancer cachexia [50][51][52]. Proinflammatory cytokines with catabolic actions, in particular, IL-6, IL-1β, TNFα and IFNγ, seem to be key mediators of cancer cachexia and it has been proposed that crosstalk between tumor cells, the immune system and the specific cell composition of the TME are crucial to the releasing of these factors [53,54]. In line with this, we observed a strong reduction of IL-1β expressing macrophages, NK cells, DC and CD3 + cells in the TME of PD-H-infected Colon-26 tumors demonstrating that the immunomodulating properties of PD-H contributed to the reduction of IL-1β-expressing immune cells, which may also affect cachexia development.…”

M5C regulator-mediated methylation modification patterns and tumor microenvironment infiltration characterization in lung adenocarcinoma

“…An increasing number of studies have shown that the TME has a crucial impact on tumor progression, immunotherapy response, and immune escape (20,21). Recently, one research has also showed that under a scenario of balanced autophagy in the tumor microenvironment, the infiltrating immune cells control cytokine production and secretion (22). Sacco et al indicated that tumor-infiltrating immune cells could affect the tumor immunosurveillance by regulating the iron metabolism (23).…”

The Role of Autophagy Modulated by Exercise in Cancer Cachexia

“…Research shows that the size of cancerous tissue is not associated with the presence of cachexia, but that the stage of cancer can affect the severity of cachexia. The prevalence of cancer cachexia is approximately 50% in all patients with cancer, increasing to 80% according to the disease progression [5]. Almost 80% of patients with gastric or pancreatic cancer and 50% of patients with lung, prostate, or colon cancer experience cachexia.…”

“…The pathogenesis of cancer cachexia is systemic inflammation caused by the interaction between tumor and organ tissues, resulting in alterations to the metabolism and homeostasis in different parts of the body [5]. Cancer cachexia ultimately affects the skeletal muscle, but its effect is also found in other tissues, such as the cardiac muscle and liver [7].…”

“…As such, understanding the phase of cancer is important for recognizing the importance of autophagy activity. For cancer cachexia, which more prominently occurs in the later stages of cancer, the disbalance of autophagy causes uncontrolled cytokine production and secretion by inflammatory cells in the tumor and other organs [5]. Until recently, it has been debated whether using an autophagy modulator for cancer therapy is a wise decision, considering that autophagy also plays an important role in physiological functioning to maintain homeostasis [10].…”