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Nat. Rev. Canc, 7, 834

Nat. Rev. Canc, 7, 834. Tumor cells are: Intravasating Circulating Homing/Arresting Extravasating Initiating & maintaining growth in new environment. Looking at secondary tumor sites:. Premetastatic Micrometastases (pre angiogenic) Metastases. <-- From where? --> Dormancy?.

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Nat. Rev. Canc, 7, 834

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  1. Nat. Rev. Canc, 7, 834

  2. Tumor cells are: • Intravasating • Circulating • Homing/Arresting • Extravasating • Initiating & maintaining growth • in new environment Looking at secondary tumor sites: Premetastatic Micrometastases (pre angiogenic) Metastases <-- From where? --> Dormancy?

  3. “What is it that decides which organ shall suffer in a case of disseminated cancer?”- 1889, Paget • “Seed and Soil” • organ specificity depends on tumor cell and 2° site • Blood Flow Patterns determine sites (1920s) • 66% consistent with blood flow • 14% fewer mets than expected • 20% more mets than expected • Therefore a combined theory… • Blood flow then compatibility • -1992, Weiss • Premetastatic Niche conditioning

  4. Chambers et al, Nature Reviews Cancer (2002), 2, 563

  5. “What is it that decides which organ shall suffer in a case of disseminated cancer?”- 1889, Paget • “Seed and Soil” • organ specificity depends on tumor cell and 2° site • Blood Flow Patterns determine sites (1920s) • 66% consistent with blood flow • 14% fewer mets than expected • 20% more mets than expected • Therefore a combined theory… • Blood flow then compatibility • -1992, Weiss • Premetastatic Niche conditioning

  6. “Class Action”/ Community effects • Heterogeniety of cells in tumor population • Clustered Migration of Tumor Cells • ECM degradation • Paracrine Loops • (signaling /adhesion) • Temporal Cooperation • successive waves of cancer cells passing by • induce progressive changes

  7. Head-Neck Tumor Reacquisition/ Presence of uPAR on cells- growth of disseminated cells Aguirre-Ghiso, J., Nat. Rev. Canc, 7, 834

  8. “pre”metastatic niche - do metastatic tumors affect host tissues, either locally around the tumor, or systemically? tumor cells and: - endothelium (vascular, lymphatic) - immune cells (local, from BM) - fibroblasts/stroma

  9. Tumor cells and endothelium: -lots of experiments from the 1990’s show that cytokine injection (IL-1, IL-6, TNFa) activate endothelim and promote subsequent tumor (tail vein met assays) formation Orr FW et.al., Am J Pathol 190: 310-329

  10. Tumor cells and endothelium: integrins adhesion at rest adhesion under flow Orr FW et.al., Am J Pathol 190: 310-329

  11. Tumor cells and endothelium: selectins Lots of data on sel. upregulation by cytokines and tumor cells, but this is nice: a mouse model with transgenic E-selectin + B16 cells engineered to express selectin ligands changes the pattern of tumor metastasis Biancone L et.al., J Exp Med 183: 581-587

  12. Tumor cells and endothelium: direct activation IL-1 TNFa lung liver both E-selectin Injected tumor cells can induce cytokine production and endothelial changes in the liver (met site) Khatib A et.al., Cancer Res 59: 1356-61

  13. Tumor cells and endothelium: direct activation Cytokines actually made by immune cells (Kupffer?) in the liver; By confocal microscopy, adhesion molecule induction leads to tumor cell extravasation Met. tumor cells GFP tumor F4/80 (Kupffer?) TNFa Non-met. tumor cells Point though: Known that most of these extravasating cells will not survive Khatib A et.al., Am J Pathol 167: 749-759

  14. Tumor cells and lymphatic metastasis/niche Rinderknecht M, Detmar M J Cell Physiol 216: 347-354

  15. Tumor cells and lymphatic metastasis/niche Keratin 14-driven GFP+VEGFA or VEGFC; chemical-induced melanoma model Rinderknecht M, Detmar M J Cell Physiol 216: 347-354

  16. Tumor cells and lymphatic metastasis/niche Lymphatics/Lyve1 HEV/CD31 Prox1 BrdU Tumor can influence downstream tissue and make it more hospitable for metastasis. Argue secreted factors, but do they really exclude circulating cells? Hirakawa S et.al., J Exp Med 201: 1089-1099

  17. Tumor cells and bone marrow-derived cells tumor Definite clinical/mouse evidence to indicate that some bone marrow-derived cells (BMDCs) are mobilized into blood in cancer. Not clear: what induces mobilization (secreted factors like VEGF? tumor cells in BM?); what exactly these cells are; what they do for tumor Whetton AD, Graham GJ Trends Cell Biol 9: 233-238

  18. Systemic tumor effect: metastatic niche in the lung -benign F2; B16; LLC; 3LL highly metastatic cells inj. s.c. into nude mice, extract lungs on d.14, microarray - what is upregulated in “pre-metastatic” (section staining; PCR) lungs? -top two proteins are secreted chemokine-like molecules, S100A8 and A9 -expressed by Mac1+ myeloidy cells and by lung endothelial cell, not by tumor cells -more Mac1+ cells in pre-metastatic lungs Hiratsuka S et.al., Nature Cell Biol 8 (12): 1369-1375

  19. Systemic tumor effect: metastatic niche in the lung -what does tumor secrete to induce S100A8/9 expression? apparently, TNFa/TGFb/VEGFA: Hiratsuka S et.al., Nature Cell Biol 8 (12): 1369-1375

  20. Systemic tumor effect: metastatic niche in the lung -S100A8/9 promote mac. and tumor cell migration in vitro -Mac and endothelial cells stimulated with S100A8 promote tumor cell migration (TNFa, MIP2, TGFb - p38 for migration) Hiratsuka S et.al., Nature Cell Biol 8 (12): 1369-1375

  21. Systemic tumor effect: metastatic niche in the lung -blocking S100A8/9 reduces # myeloid cells and metastasis (never show late time points, though - 24hr maximum) Hiratsuka S et.al., Nature Cell Biol 8 (12): 1369-1375

  22. Systemic tumor effect: metastatic niche in the lung TNFa, MIP2, TGFb, S100A8/9 Hiratsuka S et.al., Nature Cell Biol 8 (12): 1369-1375

  23. Premetastatic Niche: Timing of molecular and cellular changes HPC express VEGFR1 Induction not dependent on presence of tumor cells

  24. Intradermal, SubQ & tail vein injection tumor models LLC- metastasize to lung B16- metastasize to lung, liver, spleen, kidney using 2 x 106 cells Focus on the recruitment of HPCs in the premetastatic niche Histology/Immunohistochemistry FACS

  25. FACS FN expression in lungs BMDC/HPCs Solitary Tumor Cells &EPCs Micrometastases Day 3 Day 8 Day 14 Day 18 Day 23 -2 days -1-2 days

  26. Day 14 BMD clusters Day 23 µmets >irradiation <LLC implantn Day 18 lung -gal BM met BM B16 VEGFR1

  27. VEGFR1 BM VEGFR1 CD133 VEGFR1 CD117 Day 14 BMDC are HPCs with stem/progenitor markers similar VEGFR1 expression in cellular clusters in pre-metastatic human tissue (lymph nodes) breast, lung, gastrointestinal Blockade of VEGFR1+ cells (Ab): decrease clusters, µmet

  28. VEGFR1  VEGFR1 Id3 Day 14 > cluster   Id < integrins Release s Kit-ligand VEGF-A Xpression enhanced by FN intxn Anti alpha 4 integrin MMP-9 KO --> decrease clusters, µmet Id3 KO decrease R1+ HPC in circ (654 v 3283) rescue cluster/µmet w/HPCs from wt

  29. Rescue in Id3 KO

  30. LLC FN PDGFR No tumor Day 3 Day 14 B16 FN qRT-PCR lungs

  31. Conditioned media experiments: Established clusters after MCM treatment/ Tail vein B16 1 day 4 days Media alone B16 conditioned media (lone Tumor cell) BMDCs/Tumor HPC clusters

  32. Treat mice with conditioned B16 media before and after Intradermal LLC- redirect metastases Spleen Kidney Intestine Oviduct What redirects?

  33. Pre-metastatic niche in lymph node Primary Breast Tumor Micrometastatic/metastatic niche Kaplan and Lyden reviews

  34. Open questions… Is the premetastatic niche real? What tumor derived signals target BMDCs to tissue-specific sites? Genetic/Chemokine Expression Profile Is BMDC localization random or to specific sites within target organs? ie Selective upregulation of S100A8/A9 or throughout lungs What exactly is the function of VEGFR1+ HPCs in “niche”? Do they remain undifferentiated? Do they return to BM? Do they incorporate into tumor vasculature? What exactly are the Mac1+ cells, are they functioning like HPCs? How exactly are both HPCs and Mac1+ cells enhancing disseminated tumor cell recruitment? changes endothelium…MMP activation (is there)…

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