Pathophysiology
II-31. Secondary disorders caused by tumors (2): systemic consequences
腫瘍による二次的障害（2）：癌の全身的影響
Systemic Inflammation
- mGPS (modified Glasgow Prognostic Score): ↓serum albumin + ↑CRP → predicts cachexia & survival
- Causes: tumor-produced factors (MMP, IL-1–6, TNF-α, growth factors VEGF/PDGF/FGF, chemokines); liver acute-phase proteins (CRP); immune response to tumor; BM depression → infections; clearance of therapy-killed tumor cells
Cachexia Syndrome
- Definition: weight loss >5%/12 mo; muscle breakdown (sarcopenia — skeletal + cardiac); ± fat depletion; anorexia
- Accompanied by systemic inflammation; BMI + weight loss predict survival
- Develops via ↓food intake (CNS-driven appetite loss) + ↑total energy expenditure (inflammation, ↑catabolism)
- Metabolic mechanism: tumor anaerobic glycolysis (only 2 ATP/glucose) → consumes glucose from surrounding cells → ↓blood glucose → hepatic gluconeogenesis → uses AA + glycerol → stimulates proteolysis + lipolysis
- Tumor secretome: TNF-α (strongest, → IL-6, IL-1) → gluconeogenesis, lipolysis, proteolysis, CRP; crosses BBB → β-adrenergic → adipose browning (↑uncoupling proteins → heat); TGF-β family (myostatin, adrenomedullin) → white adipose
- CNS: IL-6/IL-1 directly ↓appetite; β-adrenergic indirect; IL-1 → COX → PGE2 (anorexigenic)
Cachexia Treatment
- Causal: eliminate tumor (cachexia can’t be fully reversed without it); inhibit catabolism; reduce inflammation — steroids (effective but immunosuppressive → palliative only), NSAIDs (less effective, no cancer progression)
- Symptomatic: appetite stimulants, liquid nutrition, exercise/physiotherapy, β-blockers (partial), anti-TNF-α (partial), COX inhibitors (aspirin/COX-2)
Tumor Pain
- Nociceptive: tumor + inflammatory cells produce mediators → stimulate nerve endings → brain; vasodilatory mediators from nerve endings
- Neuropathic: nerve damage/dysfunction — tumor infiltration/compression, chemo-induced peripheral neuropathy
- Treatment (WHO ladder): NSAIDs (aspirin, paracetamol, ibuprofen, COX-2); weak opioids (codeine, tramadol); strong opioids (morphine, fentanyl) — opioids palliative
一問一答
▶What is the modified Glasgow Prognostic Score (mGPS)?
Low serum albumin + high CRP, which predicts cachexia and survival.
▶What tumor-produced factors drive systemic inflammation in cancer?
MMPs, IL-1–6, TNF-α, growth factors (VEGF/PDGF/FGF), and chemokines; the liver responds with acute-phase proteins (CRP).
▶Through what two broad processes does cachexia develop?
Reduced food intake (CNS-driven appetite loss) and increased total energy expenditure (inflammation, increased catabolism).
▶How is cancer cachexia defined?
Weight loss >5% over 12 months, muscle breakdown (skeletal + cardiac sarcopenia), ± fat depletion, and anorexia.
▶Describe the metabolic mechanism linking tumor glycolysis to cachexia.
Tumor anaerobic glycolysis (only 2 ATP/glucose) consumes glucose from surrounding cells → ↓blood glucose → hepatic gluconeogenesis using amino acids + glycerol → stimulates proteolysis and lipolysis.
▶What is the strongest tumor secretome factor in cachexia and its effects?
TNF-α (which induces IL-6 and IL-1) drives gluconeogenesis, lipolysis, proteolysis, and CRP, and crosses the BBB.
▶How does TNF-α cause adipose browning in cachexia?
It crosses the BBB and acts via β-adrenergic signaling to increase uncoupling proteins, producing heat (browning).
▶How do cytokines reduce appetite centrally in cachexia?
IL-6/IL-1 directly decrease appetite, β-adrenergic signaling acts indirectly, and IL-1 drives COX → PGE2 (anorexigenic).
▶Why can cachexia not be fully reversed, and what is the causal treatment?
It cannot be fully reversed without eliminating the tumor; causal treatment removes the tumor, inhibits catabolism, and reduces inflammation.
▶Why are steroids used only palliatively in cachexia?
They are effective at reducing inflammation but are immunosuppressive, limiting them to palliative use.
▶What symptomatic treatments are used for cachexia?
Appetite stimulants, liquid nutrition, exercise/physiotherapy, β-blockers (partial), anti-TNF-α (partial), and COX inhibitors (aspirin/COX-2).
▶Distinguish nociceptive and neuropathic tumor pain.
Nociceptive pain comes from tumor/inflammatory mediators stimulating nerve endings; neuropathic pain comes from nerve damage (tumor infiltration/compression, chemo-induced peripheral neuropathy).
▶How do BMI and weight loss relate to cancer prognosis?
Both BMI and degree of weight loss predict survival in cachectic cancer patients.
▶Outline the WHO analgesic ladder for tumor pain.
NSAIDs (aspirin, paracetamol, ibuprofen, COX-2) → weak opioids (codeine, tramadol) → strong opioids (morphine, fentanyl, palliative).
▶Which TGF-β family factors act on white adipose tissue in cachexia?
Myostatin and adrenomedullin.
▶Why is NSAID use favorable over steroids for reducing cancer inflammation?
NSAIDs are less effective but do not promote cancer progression (unlike immunosuppressive steroids).
▶Besides tumor factors, what else contributes to systemic inflammation in cancer?
The immune response to the tumor, bone marrow depression leading to infections, and clearance of therapy-killed tumor cells.
▶Why does tumor anaerobic glycolysis consume so much host glucose?
It yields only 2 ATP per glucose, so the tumor consumes large amounts of glucose from surrounding cells.
▶What types of muscle are wasted in cancer sarcopenia?
Both skeletal and cardiac muscle.
▶How does hepatic gluconeogenesis in cancer accelerate tissue wasting?
It uses amino acids and glycerol as substrates, stimulating proteolysis and lipolysis, which depletes muscle and fat.