Pathology in TME Issue

Matrix(stroma) is included in your study? 

  • Cell-cell interaction/cell-matrix interaction/integral TME
  • 75% quantity
  • Mechanical stiffness manisfested as desmoplasia vs. fibrosis vs. elastosis? Hypoxic survival-related changes? 
  • Edema or myxoid degeneration by activated MMP prior to neovascularization? 

Peri/intratumoral inflammatory TME?

  • chemo/cytokine by TAM ½ 
  • Double-edged sword for tumor/friend or foe?  

Invasion onset biomarker

  • For very early onset of microinvasion? lymphovascular invasion implicaiton? 

Metastasis plasticity-differentiation? Molecular similarity?

  • Lastency/dormancy? CTC? Colonization?    

TME “seed-soil”&“Ping-pong”

Stephen Paget seed-soil

  • 1994:  76 articles
  • 2004:  331 (3 folds/1decade)
  • 2010: 4861 (15 folds/ half decade)

Post-Paget era 

  • ‘Ping-pong’ experiments (IP Witz  Cancer Res, 1989)
    • BALB/c 3T3 in vitro- in vivo injection (ping)
    • Recultured from in vivo tumor (pong)
    • In vivo passage cells was considerably augmented as compared to that of in vitro maintained clonal ancestors.
    • In vivo “TME induces of pro-tumor effect.”
  • Class II cancer gene  (R. Sager PNAS, 1997)
    • Many of class II genes are regulated by TME.
    • Shifting focus from DNA to RNA

Non-tumor cells in TME are different from those in normal ME.

  • Structural and functional alteration in TME
  • Paracrine signal from tumor cell or normal cell
  • Promalignant factors in TME
  • Hypoxia (necrosis) in TME
  • Low glucose concentration in TME


  • Normalization of abnormal non-tumor constituents may reduce the malignancy phenotype?
  • Tumor reversion is, indeed, possible?
  • Not sufficiently cured  by tumor cell eradication alone?
  • Is there a hierarchy of interaction?

Tumor microenvironment
- Double-edged sword


Contemporary issue

  • Cellular/ soluble factors

– Balance score of pro-(MCP-1, IL-6, MMP) and anti-malignant (IP-10)   factors: 1.36~ 2.44 (Witz, IJCa 2003)


  • P-P interaction
  • Tumor heterogeneity vs. signal heterogeneity
  • Cross-talk (agonistic vs. antagonistic)

– TNF family

Proinflammatory cytokine as promalignant effect (since R. Virchow, 1863)

– TGF-β

> Inhibit normal mammary epithelail cells

> Enhance tumor cell invasion/mets:
loss of anti-proliferative role
– mutation in TGFBR
– inhibition of SMAD pathway
– suppressing anti-tumor immune response
– augmenting angiogenesis


Extracellular Matrix (ECM)

  • Compression buffer with structural frame
  • Cell-cell interaction regulation
    • Blackbox (footpath)
    • One thing arises from all things, and all things arise from one thing (Aristotle)
  • Tumor migration
    • Stiffness and destruction
  • No de novo synthesis

 ◊ Proteoglycan

√ Heparan sulfate

√ Chondroitin sulfate

√ Keratan sulfate

  ◊ Non-proteoglycan

√ Fiber

√ Fibronectin
√ Collagen-14 types
√ Elastin
√ Laminin

√ Hyaluronic acid

Soil researcher as in Scientific Botanist