Cachexia Anorexia Syndrome and Associated Metabolic Dysfunction in Peritoneal Metastasis
Patients with peritoneal metastasis (PM) of gastrointestinal and gynecological origin present with a nutritional deficit characterized by increased resting energy expenditure (REE), loss of muscle mass, and protein catabolism. Progression of peritoneal metastasis, as with other advanced malignancies...
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doaj-ce00d1963ba24f95b55fb695ece54ff72020-11-25T01:43:55ZengMDPI AGInternational Journal of Molecular Sciences1422-00672019-10-012021544410.3390/ijms20215444ijms20215444Cachexia Anorexia Syndrome and Associated Metabolic Dysfunction in Peritoneal MetastasisRami Archid0Wiebke Solass1Clemens Tempfer2Alfred Königsrainer3Michael Adolph4Marc A. Reymond5Robert B. Wilson6Department of General & Transplant Surgery, University Hospital Tübingen, D-72076 Tübingen, GermanyNational Center for Pleura and Peritoneum, University Hospital Tübingen, D-72076 Tübingen, GermanyDepartment of Gynecology and Obstetrics, Ruhr-University Bochum, 44625 Herne, GermanyDepartment of General & Transplant Surgery, University Hospital Tübingen, D-72076 Tübingen, GermanyNutrition Unit, Department of Anesthesiology, University Hospital Tübingen, D-72076 Tübingen, GermanyDepartment of General & Transplant Surgery, University Hospital Tübingen, D-72076 Tübingen, GermanyDepartment of Upper Gastrointestinal Surgery, UNSW, Liverpool Hospital, Sydney, NSW 2170, AustraliaPatients with peritoneal metastasis (PM) of gastrointestinal and gynecological origin present with a nutritional deficit characterized by increased resting energy expenditure (REE), loss of muscle mass, and protein catabolism. Progression of peritoneal metastasis, as with other advanced malignancies, is associated with cancer cachexia anorexia syndrome (CAS), involving poor appetite (anorexia), involuntary weight loss, and chronic inflammation. Eventual causes of mortality include dysfunctional metabolism and energy store exhaustion. Etiology of CAS in PM patients is multifactorial including tumor growth, host response, cytokine release, systemic inflammation, proteolysis, lipolysis, malignant small bowel obstruction, ascites, and gastrointestinal side effects of drug therapy (chemotherapy, opioids). Metabolic changes of CAS in PM relate more to a systemic inflammatory response than an adaptation to starvation. Metabolic reprogramming is required for cancer cells shed into the peritoneal cavity to resist anoikis (i.e., programmed cell death). Profound changes in hexokinase metabolism are needed to compensate ineffective oxidative phosphorylation in mitochondria. During the development of PM, hypoxia inducible factor-1α (HIF-1α) plays a key role in activating both aerobic and anaerobic glycolysis, increasing the uptake of glucose, lipid, and glutamine into cancer cells. HIF-1α upregulates hexokinase II, phosphoglycerate kinase 1 (PGK1), pyruvate dehydrogenase kinase (PDK), pyruvate kinase muscle isoenzyme 2 (PKM2), lactate dehydrogenase (LDH) and glucose transporters (GLUT) and promotes cytoplasmic glycolysis. HIF-1α also stimulates the utilization of glutamine and fatty acids as alternative energy substrates. Cancer cells in the peritoneal cavity interact with cancer-associated fibroblasts and adipocytes to meet metabolic demands and incorporate autophagy products for growth. Therapy of CAS in PM is challenging. Optimal nutritional intake alone including total parenteral nutrition is unable to reverse CAS. Pressurized intraperitoneal aerosol chemotherapy (PIPAC) stabilized nutritional status in a significant proportion of PM patients. Agents targeting the mechanisms of CAS are under development.https://www.mdpi.com/1422-0067/20/21/5444cancer cachexiacachexia anorexia syndromeperitoneal metastasiscancer metabolism |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Rami Archid Wiebke Solass Clemens Tempfer Alfred Königsrainer Michael Adolph Marc A. Reymond Robert B. Wilson |
spellingShingle |
Rami Archid Wiebke Solass Clemens Tempfer Alfred Königsrainer Michael Adolph Marc A. Reymond Robert B. Wilson Cachexia Anorexia Syndrome and Associated Metabolic Dysfunction in Peritoneal Metastasis International Journal of Molecular Sciences cancer cachexia cachexia anorexia syndrome peritoneal metastasis cancer metabolism |
author_facet |
Rami Archid Wiebke Solass Clemens Tempfer Alfred Königsrainer Michael Adolph Marc A. Reymond Robert B. Wilson |
author_sort |
Rami Archid |
title |
Cachexia Anorexia Syndrome and Associated Metabolic Dysfunction in Peritoneal Metastasis |
title_short |
Cachexia Anorexia Syndrome and Associated Metabolic Dysfunction in Peritoneal Metastasis |
title_full |
Cachexia Anorexia Syndrome and Associated Metabolic Dysfunction in Peritoneal Metastasis |
title_fullStr |
Cachexia Anorexia Syndrome and Associated Metabolic Dysfunction in Peritoneal Metastasis |
title_full_unstemmed |
Cachexia Anorexia Syndrome and Associated Metabolic Dysfunction in Peritoneal Metastasis |
title_sort |
cachexia anorexia syndrome and associated metabolic dysfunction in peritoneal metastasis |
publisher |
MDPI AG |
series |
International Journal of Molecular Sciences |
issn |
1422-0067 |
publishDate |
2019-10-01 |
description |
Patients with peritoneal metastasis (PM) of gastrointestinal and gynecological origin present with a nutritional deficit characterized by increased resting energy expenditure (REE), loss of muscle mass, and protein catabolism. Progression of peritoneal metastasis, as with other advanced malignancies, is associated with cancer cachexia anorexia syndrome (CAS), involving poor appetite (anorexia), involuntary weight loss, and chronic inflammation. Eventual causes of mortality include dysfunctional metabolism and energy store exhaustion. Etiology of CAS in PM patients is multifactorial including tumor growth, host response, cytokine release, systemic inflammation, proteolysis, lipolysis, malignant small bowel obstruction, ascites, and gastrointestinal side effects of drug therapy (chemotherapy, opioids). Metabolic changes of CAS in PM relate more to a systemic inflammatory response than an adaptation to starvation. Metabolic reprogramming is required for cancer cells shed into the peritoneal cavity to resist anoikis (i.e., programmed cell death). Profound changes in hexokinase metabolism are needed to compensate ineffective oxidative phosphorylation in mitochondria. During the development of PM, hypoxia inducible factor-1α (HIF-1α) plays a key role in activating both aerobic and anaerobic glycolysis, increasing the uptake of glucose, lipid, and glutamine into cancer cells. HIF-1α upregulates hexokinase II, phosphoglycerate kinase 1 (PGK1), pyruvate dehydrogenase kinase (PDK), pyruvate kinase muscle isoenzyme 2 (PKM2), lactate dehydrogenase (LDH) and glucose transporters (GLUT) and promotes cytoplasmic glycolysis. HIF-1α also stimulates the utilization of glutamine and fatty acids as alternative energy substrates. Cancer cells in the peritoneal cavity interact with cancer-associated fibroblasts and adipocytes to meet metabolic demands and incorporate autophagy products for growth. Therapy of CAS in PM is challenging. Optimal nutritional intake alone including total parenteral nutrition is unable to reverse CAS. Pressurized intraperitoneal aerosol chemotherapy (PIPAC) stabilized nutritional status in a significant proportion of PM patients. Agents targeting the mechanisms of CAS are under development. |
topic |
cancer cachexia cachexia anorexia syndrome peritoneal metastasis cancer metabolism |
url |
https://www.mdpi.com/1422-0067/20/21/5444 |
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