Breast cancer is one of the most common female cancers and known to metastasize to brain. It is acknowledged that brain prevents the entering of substances in the blood stream by blood-brain barrier (BBB) and only tiny materials can across the BBB. In terms of size, cancer cells are too large to penetrate the BBB. However, 30% of all women with metastatic breast cancer develop brain tumors. Recently, many studies have suggested that the reciprocal interaction between cancer cells and environment is important for cancer metastasis. Therefore, it is plausible that tumor microenvironment is involved in breast cancer brain metastasis. Our research is to understand the role of Interface Zone in breast cancer brain metastasis.
Category: Tumor Microenvironment (TME)
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)
– No MECE
- 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
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
Question?
- 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)
– No MECE
- 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
Cancer Interface Microenvironment Laboratory 
