Cancer Cachexia Pathophysiology and Translational Aspect of Herbal Medicine

Abstract

About half of all cancer patients show a syndrome of cachexia, characterized by anorexia and loss of adipose tissue and skeletal muscle mass. Numerous cytokines have been postulated to play a role in the etiology of cancer cachexia. Cytokines can elicit effects that mimic leptin signaling and suppress orexigenic ghrelin and neuropeptide Y signaling, inducing sustained anorexia and cachexia not accompanied by the usual compensatory response. Furthermore, cytokines have been implicated in the induction of cancer-related muscle wasting. In particular, tumor necrosis factor-alpha, interleukin-1, interleukin-6 and interferon-gamma have been implicated in the induction of cancer-related muscle wasting. Cytokine-induced skeletal muscle wasting is probably a multifactorial process, which involves a depression in protein synthesis, an increase in protein degradation or a combination of both. Cancer patients suffer from the reduction in physical function, tolerance to anti-cancer therapy and survival, while many effective chemotherapeutic agents for cancer are burdened by toxicities that can reduce patient's quality of life or hinder their effective use. Herbal medicines have been widely used to help improve such conditions. Recent studies have shown that herbal medicines such as rikkunshito enhance ghrelin signaling and consequently improve nausea, appetite loss and cachexia associated with cancer or cancer chemotherapy, which worsens the quality of life and life expectancy of the patients. The multicomponent herbal medicines capable of targeting multiple sites could be useful for future drug discovery. Mechanistic studies and identification of active compounds could lead to new discoveries in biological and biomedical sciences.

Pancreatic cancer cachexia: a review of mechanisms and therapeutics

“…These inputs are transduced into neuronal responses and, via signaling pathways, behavioral responses. Current evidence suggests that systemic inflammation plays a critical role in inducing cancer anorexia by triggering a complex neurochemical cascade (Laviano et al, 2003; Fearon et al, 2013; Suzuki et al, 2013; Tuca et al, 2013). Increased cytokine expression from tumor growth prevents the hypothalamus from responding appropriately to peripheral signals by persistent stimulation of anorexigenic pathways and inhibition of orexigenic pathways (Suzuki et al, 2013; Tuca et al, 2013).…”

Pancreatic Cancer Cachexia: Current Concepts and Clinical Management

“…Anorexia and hypercatabolism have been found in cachectic patients to be driven by mechanical factors such as cytokines, circulating hormones, neuropeptides, neurotransmiters, and tumor-derived factors. Recent studies have also identiied other processes that potentially contributed to the pathophysiology of pancreatic cancer cachexia, including neural invasion and abnormalities in muscle microenvironment [20][21][22][23][24][25]. The following section will review these currently proposed mechanisms that interact and contribute to the development of this disease.…”

“…In some animal and clinical studies, leptin levels were found to not be elevated in tumor-bearing rats and patients with cancer cachexia [38][39][40][41]. Recent research demonstrated that in cancer cachexia, IL-1 and TNF-α mimic leptin signaling and result in the interference of the orexigenic pathway, which is normally a response to reduced leptin levels [24,42]. This suggests that even during starvation, the inhibition of the orexigenic response and activation of the anorexigenic pathway can occur and lead to unopposed anorexia and elevated energy expenditure.…”

“…A mechanical response is produced via these signaling pathways and abnormalities in these pathways can lead to anorexia. Current indings indicate that systemic inlammation plays a role in inducing cancer anorexia through the activation of a complex neurochemical cascade [24,25,31,32]. Interference with the hypothalamus' normal response to peripheral signals is suggested to be a direct consequence of elevated tumormediated cytokine expression, which actively promotes anorexigenic pathways and inhibits orexigenic pathways [24,25].…”

“…Current indings indicate that systemic inlammation plays a role in inducing cancer anorexia through the activation of a complex neurochemical cascade [24,25,31,32]. Interference with the hypothalamus' normal response to peripheral signals is suggested to be a direct consequence of elevated tumormediated cytokine expression, which actively promotes anorexigenic pathways and inhibits orexigenic pathways [24,25].Derangements in the ability of the hypothalamus to transduce peripheral signals into neuronal responses may also be associated with cancer anorexia. There are two pathways that are responsible for energy expenditure and food intake within the hypothalamus: neuropeptide Y (NPY)/ agouti-related peptide (AgRP) neurons that stimulate energy intake and proopiomelanocortin (POMC)/cocaine and amphetamine-regulated transcript (CART) neurons that inhibit intake.…”