Underlying Mechanisms and Therapy of Cancer Cachexia-Anorexia (Week 6 Lecture 1) Flashcards
What factors [concurrently] contribute to the genesis and evolution of wasting in cancer?
- Tumor-intrinsic factors: primary site, mutations, stage, size & metabolic activity, over-expression of catabolic effector molecules, elicited immune response and proinflammatory effector molecules & cells
- Patient intrinsic factors: sex, older age, comorbidity, genetics
- Treatment specific factors: Toxicities associated with impaired dietary intake “nutrition impact symptoms”, cell/tissue specific toxicities (muscle and adipose direct wasting signals)
What are the 4 domains for the conceptual framework of anorexia cachexia of cancer?
- depletion of reserves
- limitation of food intake
- catabolic drivers (metabolites and signalling pathways in mayhen)
- impact and outcomes
relationship between cachexia and malnutrition
Cachexia is disease-associated malnutrition, and is in part defined by the presence of underlying disease
How is cachexia characterized?
ongoing loss of skeletal muscle
mass (with or without loss of fat mass)
* clinical importance: mortality, chemotherapy induced toxicity, poor outcomes (infection)
* symptoms: fatigue, dispnea
* impaired function: decreased activity, worse quality of life
How is long-term energy controlled in healthy individuals?
Peripheral signals are sensed and processed by the hypothalamus and brainstem. These signals are integrated with hedonic, emotional and environmental influences via higher cortical centers and the limbic system to generate feelings of satiety and hunger and maintain stable body weight.
* energy intake = TEE
How does the tumour drive muscle wasting?
- Tumor mass consumes energy and nutrients - basically an extra organ with needs of its own
- Tumor secretes molecules which profoundly
alter metabolism and catabolism. disturbing body homeostasis
How does weight loss follow cancer progression?
Muscle and fat losses mirror metastatic progression (of colorectal cancer)
* Loss of muscle and fat as it trajectory toward end stage and see lots of LBM and FM and gets faster over time during the cancer. See an exponential rise in the mass of the tumour and can see it is taking away from the rest of the body.
How can the energetic cost of cancer be measured?
Can assess the size of the tumour %ATP production from energy metabolism to determine how many calories it takes away from the rest of the body
* Cancer can behave in part as a large parasite
Overall model if of the wasting process
Catabolic effector molecules produced by tumour can enter circulation and convey certain messages. The way it interacts with the immune system can result in the expression of molecules that can launch a disturbance into the metabolism causing the person to waste away. Does 1 of 2 things
1. go straight to tissue and bind receptor and turn on a catabolic process by directly speaking to tissue
2. can speak to the central nervous system, so the brain, and induce loss of appetite and fatigue and reducing signals and and thus reduced contractile and nutrient signalling causing tissue to waste away.
lipolysis and proteolysis
CNS Mediated Mechanisms of anorexia
molecules made by tumour, IL1 beta, TNF-a, GDF 15 act on hypo to inhibit appetitie
* Cancer makes people uninterested in eating right from the get go. No perception of appetite or hunger. When they do eat they may feel as they have been immediately stuffed or nauseas so every aspect of desire to eat is implicated in cancer.
Tumor-driven catabolism in the muscles
Degradation and break down signals are favoured. Tumours make molecules that are direct actors and muscles have receptors for these. The tumour makes excess of these and so see break down and dysfunction of myofibrils and get loss of function
How do tumours effect lypolysis?
- Abnormal sensitivity to physiological lipolytic stimuli: Catecholamines (norepinephrine)
- Tumor over-expression of lipolysis – inducing factors: Adrenomedullin
catacholamine effect in lipolysis
100% higher hormone-sensitive lipase protein expression in human adipose tissue of pancreas cancer patients with weight loss; 100% higher plasma free fatty acids
* Higher stimulus of norepinephrine
Adrenomedullin effect on lipolysis
Exosomes are cell-derived vesicles. Pancreatic cancer exosomes contain a payload of adrenomedullin a potent activator of lipolysis in subcutaneous adipocytes
* Some molecules in cytplasm can leave cancer by process if blebbing and blobs off going to othe cells and bleb in. And join another membrane and send the contents into the cell.
How is chemotherapy grouped?
- Grouped into different classes based on mechanism of action.
- Drugs of different classes are combined to increase antitumor effects.
- Drugs in different classes have different side effect profiles: Combination therapy often based on avoiding overlapping toxicities.
Mechanisms of cytotoxic chemotherapy
Drugs that kill any cell that happens to be dividing rapidly at point of time it is in body so tumour but also other places such as bone marrow, lining of GI
* act on rapidly dividing cancer and normal cells
* Alkylating agents interfere with DNA base pairing, leading to strand breaks.
* Topoisomerase inhibitors prevent DNA uncoiling.
* Taxanes and vinca alkaloids interfere with microtubule function required for mitosis.
* Antimetabolites block the formation and use of
nucleic acids.
Mechanisms of targeted therapies
Tumour scells proliferate and have a downstream of growth factors and have signalling cascades involving different mediators. If you can shoot somewhere in this can prevent proliferation. When muscle cells proliferate contains similar growth factors of the same cascade so chemo is not restricted to tumour.
* Receptor tyrosine kinases and downstream RAS/RAF/MAPK and PI3K/AKT/mTOR signaling pathways are activated for proliferation and invasion by tumor cells
* Molecular cancer therapeutics target these pathways
* Some drugs (e.g., sorafenib [Nexavar], sunitinib [Sutent], imatinib [Gleevec]) have multiple targets EGFR = epithelial growth factor receptor; VEGF = vascular endothelial growth factor.)
Mechanisms of immuno- therapies
The goal of cancer immunotherapy is to boost the ability of the immune system to detect and destroy cancer cells by overcoming the mechanisms by which tumors evade the immune response
* trick tumour and disable ability to hide
* special class of t-cells
How does chemotherapy effect food intake?
Nutrition impact symptoms and risk of reduced dietary intake
* nausea inducing
Treatment driven catabolism in cancer
Everything highlighted has been documented as consequence of chemo
* cytotoxic chemo can can turn on and acitvate everything
* big loss of muscle mass since treatment may also target muscle
Therapuetic options for cancer cachexia
- Nutrition
- exercise
- Drugs
- Multimodal therapy
Where should therapy target if patient has no voalition to eat?
In brain areas controlling appetite such as the arcuate nucleas
* The POMC neurons inhibit food intake and can be inhibited by glucocorticoids so effective anorexia therapy. The ACRP/NPY to launch ingestion behaviour and grow so ghrelin like compound have been investigated as therapeutics
* Nutrition therapy may be more optimized by a drug that can act to improve appetite
