![Page 1: Biology of metastasis - Columbia University · Dispersion & seeding Detec/on and removal of primary tumor Treatments for primary breast cancer 89% survival rate for localized breast](https://reader030.vdocument.in/reader030/viewer/2022040622/5d296e9d88c993f3778d3f98/html5/thumbnails/1.jpg)
Biology of metastasis
Swarnali Acharyya Nov 11, 2015
![Page 2: Biology of metastasis - Columbia University · Dispersion & seeding Detec/on and removal of primary tumor Treatments for primary breast cancer 89% survival rate for localized breast](https://reader030.vdocument.in/reader030/viewer/2022040622/5d296e9d88c993f3778d3f98/html5/thumbnails/2.jpg)
Dispersion&seedingDetec/onandremoval
ofprimarytumor
Treatments for primary breast cancer
89%survivalrateforlocalizedbreastcancers
![Page 3: Biology of metastasis - Columbia University · Dispersion & seeding Detec/on and removal of primary tumor Treatments for primary breast cancer 89% survival rate for localized breast](https://reader030.vdocument.in/reader030/viewer/2022040622/5d296e9d88c993f3778d3f98/html5/thumbnails/3.jpg)
Dispersion&seedingDetec/onandremoval
ofprimarytumor
Advances in breast cancer treatment
Over 90% survival rate for localized, well treated breast cancers
Be#erdetec)onandimaging
Newsurgicalop)ons
Targetedtherapy
![Page 4: Biology of metastasis - Columbia University · Dispersion & seeding Detec/on and removal of primary tumor Treatments for primary breast cancer 89% survival rate for localized breast](https://reader030.vdocument.in/reader030/viewer/2022040622/5d296e9d88c993f3778d3f98/html5/thumbnails/4.jpg)
Latency(monthstodecades)
Metastasisisresponsiblefor90%ofcancerdeaths
Overtmetastasis
![Page 5: Biology of metastasis - Columbia University · Dispersion & seeding Detec/on and removal of primary tumor Treatments for primary breast cancer 89% survival rate for localized breast](https://reader030.vdocument.in/reader030/viewer/2022040622/5d296e9d88c993f3778d3f98/html5/thumbnails/5.jpg)
hAp://seer.cancer.gov/staEacts/html/breast.html
![Page 6: Biology of metastasis - Columbia University · Dispersion & seeding Detec/on and removal of primary tumor Treatments for primary breast cancer 89% survival rate for localized breast](https://reader030.vdocument.in/reader030/viewer/2022040622/5d296e9d88c993f3778d3f98/html5/thumbnails/6.jpg)
Primary tumor
Metastasis
Cell-autonomous mechanisms: Genetic, epigenetic differences?
Howareprimarytumorsandmetastasisdifferent?
Non cell-autonomous mechanisms: Stromal influences
Metastasisaremoredifficulttotreatandareresistanttomostdrugs
![Page 7: Biology of metastasis - Columbia University · Dispersion & seeding Detec/on and removal of primary tumor Treatments for primary breast cancer 89% survival rate for localized breast](https://reader030.vdocument.in/reader030/viewer/2022040622/5d296e9d88c993f3778d3f98/html5/thumbnails/7.jpg)
Breast Cancer Genes
Shahetal.,Nature,2012
![Page 8: Biology of metastasis - Columbia University · Dispersion & seeding Detec/on and removal of primary tumor Treatments for primary breast cancer 89% survival rate for localized breast](https://reader030.vdocument.in/reader030/viewer/2022040622/5d296e9d88c993f3778d3f98/html5/thumbnails/8.jpg)
Mutations are highly concordant between primary tumor and metastasis Ref: Colon cancer, Brannon et al., Genome Biology, 2014
![Page 9: Biology of metastasis - Columbia University · Dispersion & seeding Detec/on and removal of primary tumor Treatments for primary breast cancer 89% survival rate for localized breast](https://reader030.vdocument.in/reader030/viewer/2022040622/5d296e9d88c993f3778d3f98/html5/thumbnails/9.jpg)
Breastcancersubtypes
Modified from: http://massgenomics.org/2012/09/a-comprehensive-atlas-of-breast-cancer-genomes.html
Luminal A slow growth and best prognosis
Luminal ca : ER positive Express luminal markers (ER alpha, cytokeratins 8/18)
Basal like triple negative cancers: worst prognosis Express basal cell markers (CK 5/6, 14, 17)
Basementmembrane
BasalorMyoepithelialcells
Luminalepithelialcells
![Page 10: Biology of metastasis - Columbia University · Dispersion & seeding Detec/on and removal of primary tumor Treatments for primary breast cancer 89% survival rate for localized breast](https://reader030.vdocument.in/reader030/viewer/2022040622/5d296e9d88c993f3778d3f98/html5/thumbnails/10.jpg)
HER2 positive breast cancer
Modified from Hongkong Breast Cancer Foundation
TargetHER2ProteinTrastuzumab
![Page 11: Biology of metastasis - Columbia University · Dispersion & seeding Detec/on and removal of primary tumor Treatments for primary breast cancer 89% survival rate for localized breast](https://reader030.vdocument.in/reader030/viewer/2022040622/5d296e9d88c993f3778d3f98/html5/thumbnails/11.jpg)
Signaling downstream of HER family
http://www.nature.com/nrclinonc/journal/v9/n1/fig_tab/nrclinonc.2011.177_F1.html
![Page 12: Biology of metastasis - Columbia University · Dispersion & seeding Detec/on and removal of primary tumor Treatments for primary breast cancer 89% survival rate for localized breast](https://reader030.vdocument.in/reader030/viewer/2022040622/5d296e9d88c993f3778d3f98/html5/thumbnails/12.jpg)
Reference: Ellis and Perou, Cancer Discovery, Jan 2013
![Page 13: Biology of metastasis - Columbia University · Dispersion & seeding Detec/on and removal of primary tumor Treatments for primary breast cancer 89% survival rate for localized breast](https://reader030.vdocument.in/reader030/viewer/2022040622/5d296e9d88c993f3778d3f98/html5/thumbnails/13.jpg)
Trends in breast cancer incidence and mortality
![Page 14: Biology of metastasis - Columbia University · Dispersion & seeding Detec/on and removal of primary tumor Treatments for primary breast cancer 89% survival rate for localized breast](https://reader030.vdocument.in/reader030/viewer/2022040622/5d296e9d88c993f3778d3f98/html5/thumbnails/14.jpg)
Metastasis: Differences in latencies in cancer types
Lung adenocarcinoma: Rapid metastasis to mutiple organs
Nature
Breast adenocarcinoma: Latency and metastatic speciation
. . . . . .
. . . . .
. . . . . .
WNT/TCF LEF1, HOXB9
EREG, COX2, FASCIN1, MMP1,
ANGPTL4, HBEGF, COX2,
FASCIN1, MMP1, ANGPTL4,
ST6GALNAC5
IL11, ADAMTS1,MMP1, TGFß, CTGF, PTHrP
miR335 miR126
![Page 15: Biology of metastasis - Columbia University · Dispersion & seeding Detec/on and removal of primary tumor Treatments for primary breast cancer 89% survival rate for localized breast](https://reader030.vdocument.in/reader030/viewer/2022040622/5d296e9d88c993f3778d3f98/html5/thumbnails/15.jpg)
Evolution of metastasis Step-wise or parallel?
![Page 16: Biology of metastasis - Columbia University · Dispersion & seeding Detec/on and removal of primary tumor Treatments for primary breast cancer 89% survival rate for localized breast](https://reader030.vdocument.in/reader030/viewer/2022040622/5d296e9d88c993f3778d3f98/html5/thumbnails/16.jpg)
Timelineofdevelopmentofmetastasisbasedonmathema)calmodeling
Luebeck,Nature,2010
![Page 17: Biology of metastasis - Columbia University · Dispersion & seeding Detec/on and removal of primary tumor Treatments for primary breast cancer 89% survival rate for localized breast](https://reader030.vdocument.in/reader030/viewer/2022040622/5d296e9d88c993f3778d3f98/html5/thumbnails/17.jpg)
ClonalEvolu)onofheterogeneousprimarytumorsgivingrisetometastasis
![Page 18: Biology of metastasis - Columbia University · Dispersion & seeding Detec/on and removal of primary tumor Treatments for primary breast cancer 89% survival rate for localized breast](https://reader030.vdocument.in/reader030/viewer/2022040622/5d296e9d88c993f3778d3f98/html5/thumbnails/18.jpg)
Alternative hypothesis: Parallel evolution of metastasis?
Bone marrow cancer cells genomically different from primary tumor mix - Spread early and evolve
OR - Different subpopulation
which might not give rise to overt metastasis?
Clinically- optimal to decide treatments based on DTCs or primary tumors?
Reference:Gray,CancerCell,2003
![Page 19: Biology of metastasis - Columbia University · Dispersion & seeding Detec/on and removal of primary tumor Treatments for primary breast cancer 89% survival rate for localized breast](https://reader030.vdocument.in/reader030/viewer/2022040622/5d296e9d88c993f3778d3f98/html5/thumbnails/19.jpg)
Phenotypically normal untransformed cells can persist in the lungs for months
Podsypanina et al., Science, 2008
![Page 20: Biology of metastasis - Columbia University · Dispersion & seeding Detec/on and removal of primary tumor Treatments for primary breast cancer 89% survival rate for localized breast](https://reader030.vdocument.in/reader030/viewer/2022040622/5d296e9d88c993f3778d3f98/html5/thumbnails/20.jpg)
Delayed oncogene induction still forms tumors
When normal mammary cells have reached the distant site in the absence of transformation at the primary site.
![Page 21: Biology of metastasis - Columbia University · Dispersion & seeding Detec/on and removal of primary tumor Treatments for primary breast cancer 89% survival rate for localized breast](https://reader030.vdocument.in/reader030/viewer/2022040622/5d296e9d88c993f3778d3f98/html5/thumbnails/21.jpg)
Seed or the soil: which matters in metastasis?
Ref: Fidler, Nat Rev Cancer, 2003
4millioncells/gofprimarytumorshed0.01%successful!
![Page 22: Biology of metastasis - Columbia University · Dispersion & seeding Detec/on and removal of primary tumor Treatments for primary breast cancer 89% survival rate for localized breast](https://reader030.vdocument.in/reader030/viewer/2022040622/5d296e9d88c993f3778d3f98/html5/thumbnails/22.jpg)
Brief history of metastasis research (Ref: Metastasis Research Society)
![Page 23: Biology of metastasis - Columbia University · Dispersion & seeding Detec/on and removal of primary tumor Treatments for primary breast cancer 89% survival rate for localized breast](https://reader030.vdocument.in/reader030/viewer/2022040622/5d296e9d88c993f3778d3f98/html5/thumbnails/23.jpg)
Metastatic cells spread through lymphatics or blood?
Blood (hematogenous spread)
Modified from www.iopscience.iop.org
Lymphatic spread
Modified from www.cancer.org
![Page 24: Biology of metastasis - Columbia University · Dispersion & seeding Detec/on and removal of primary tumor Treatments for primary breast cancer 89% survival rate for localized breast](https://reader030.vdocument.in/reader030/viewer/2022040622/5d296e9d88c993f3778d3f98/html5/thumbnails/24.jpg)
Lymphatic spread of breast cancer
![Page 25: Biology of metastasis - Columbia University · Dispersion & seeding Detec/on and removal of primary tumor Treatments for primary breast cancer 89% survival rate for localized breast](https://reader030.vdocument.in/reader030/viewer/2022040622/5d296e9d88c993f3778d3f98/html5/thumbnails/25.jpg)
• Might depend on physical restrictions on invasive tumors. • Easier to survive in passive, low shear flow. • Lymphatics more leaky, lacking tight interendothelial junctions (higher chances of intravasation).
Lymphatics more accessible to cancer cells?
Peritumoral lymphatics matter more than intratumoral lymphatics
WongandHynes,CellCycle,2006
![Page 26: Biology of metastasis - Columbia University · Dispersion & seeding Detec/on and removal of primary tumor Treatments for primary breast cancer 89% survival rate for localized breast](https://reader030.vdocument.in/reader030/viewer/2022040622/5d296e9d88c993f3778d3f98/html5/thumbnails/26.jpg)
Potential pathways of reaching circulation from the primary tumor
WongandHynes,CellCycle,2006
Inprostatecancer,84%withlymphnodespreadhavehematogenousspread.
![Page 27: Biology of metastasis - Columbia University · Dispersion & seeding Detec/on and removal of primary tumor Treatments for primary breast cancer 89% survival rate for localized breast](https://reader030.vdocument.in/reader030/viewer/2022040622/5d296e9d88c993f3778d3f98/html5/thumbnails/27.jpg)
Drug resistance of metastases: yet another problem to solve
![Page 28: Biology of metastasis - Columbia University · Dispersion & seeding Detec/on and removal of primary tumor Treatments for primary breast cancer 89% survival rate for localized breast](https://reader030.vdocument.in/reader030/viewer/2022040622/5d296e9d88c993f3778d3f98/html5/thumbnails/28.jpg)
Sensi/ve Resistant
Kuczynskietal.,NatRevClinOncol.,2013
Challengestotargetdrugresistantclones
![Page 29: Biology of metastasis - Columbia University · Dispersion & seeding Detec/on and removal of primary tumor Treatments for primary breast cancer 89% survival rate for localized breast](https://reader030.vdocument.in/reader030/viewer/2022040622/5d296e9d88c993f3778d3f98/html5/thumbnails/29.jpg)
Latency(monthstodecades)
Overtmetastasis
Animal models to study the complex process of metastasis
![Page 30: Biology of metastasis - Columbia University · Dispersion & seeding Detec/on and removal of primary tumor Treatments for primary breast cancer 89% survival rate for localized breast](https://reader030.vdocument.in/reader030/viewer/2022040622/5d296e9d88c993f3778d3f98/html5/thumbnails/30.jpg)
Transgenic mouse models of breast cancer
![Page 31: Biology of metastasis - Columbia University · Dispersion & seeding Detec/on and removal of primary tumor Treatments for primary breast cancer 89% survival rate for localized breast](https://reader030.vdocument.in/reader030/viewer/2022040622/5d296e9d88c993f3778d3f98/html5/thumbnails/31.jpg)
Development of Patient derived xenografts
Kopetz et al., Clinical Cancer research, 2012
![Page 32: Biology of metastasis - Columbia University · Dispersion & seeding Detec/on and removal of primary tumor Treatments for primary breast cancer 89% survival rate for localized breast](https://reader030.vdocument.in/reader030/viewer/2022040622/5d296e9d88c993f3778d3f98/html5/thumbnails/32.jpg)
Fresh tumor implantation in immunocompromised mice
![Page 33: Biology of metastasis - Columbia University · Dispersion & seeding Detec/on and removal of primary tumor Treatments for primary breast cancer 89% survival rate for localized breast](https://reader030.vdocument.in/reader030/viewer/2022040622/5d296e9d88c993f3778d3f98/html5/thumbnails/33.jpg)
Tumor grafts in mice resemble the donor patient tumors by histology, genomics, growth
![Page 34: Biology of metastasis - Columbia University · Dispersion & seeding Detec/on and removal of primary tumor Treatments for primary breast cancer 89% survival rate for localized breast](https://reader030.vdocument.in/reader030/viewer/2022040622/5d296e9d88c993f3778d3f98/html5/thumbnails/34.jpg)
Sitesinpa)ents SitesinmiceMETASTASISSITES
![Page 35: Biology of metastasis - Columbia University · Dispersion & seeding Detec/on and removal of primary tumor Treatments for primary breast cancer 89% survival rate for localized breast](https://reader030.vdocument.in/reader030/viewer/2022040622/5d296e9d88c993f3778d3f98/html5/thumbnails/35.jpg)
Metastasis-associatedgeneexpression
ApproachI:Interrogatetheend-products
Kang et al Cancer Cell 2003 Minn et al Nature 2005 Tavazoie et al Nature 2008 Bos et al Nature 2009
BrM
LM
BoM
43genes
54genes
102genes
Pro
babi
lity
p < 0.0001
1.0
0.8
0.6
0.4
0.2
0 0 50 100 150
LMS+TβRS+
Lung metastasis-free survival (months)
LMS: 18-gene signature associated with lung relapse
![Page 36: Biology of metastasis - Columbia University · Dispersion & seeding Detec/on and removal of primary tumor Treatments for primary breast cancer 89% survival rate for localized breast](https://reader030.vdocument.in/reader030/viewer/2022040622/5d296e9d88c993f3778d3f98/html5/thumbnails/36.jpg)
EREG COX2 MMP1 ANGPTL4 FSCN1 NEDD9 ID1 CXCL1 TNC VCAM1 CXCR4 LTBP1 ROBO1 KRTHB1 MAN1A1 KYNU C10orf116 RARRES3
BreastCancerLungMetastasisSignature(LMS)
COX2: vascular permeability Epiregulin: cell motility Fascin1: invadopodia MMP1: collagenase ANGPTL4: endothelial disjunction
Tenascin-C
VCAM-1
Gupta et al Nature 2007 Padua et al Cell 2008 Tavazoie et al Nature 2008
Kim et al Cell 2009 Oskarsson et al JACS 2010
![Page 37: Biology of metastasis - Columbia University · Dispersion & seeding Detec/on and removal of primary tumor Treatments for primary breast cancer 89% survival rate for localized breast](https://reader030.vdocument.in/reader030/viewer/2022040622/5d296e9d88c993f3778d3f98/html5/thumbnails/37.jpg)
Tumor microenvironment interactions that support tumor progression
Quail and Joyce,, Nat Med, 2013
![Page 38: Biology of metastasis - Columbia University · Dispersion & seeding Detec/on and removal of primary tumor Treatments for primary breast cancer 89% survival rate for localized breast](https://reader030.vdocument.in/reader030/viewer/2022040622/5d296e9d88c993f3778d3f98/html5/thumbnails/38.jpg)
In transit
![Page 39: Biology of metastasis - Columbia University · Dispersion & seeding Detec/on and removal of primary tumor Treatments for primary breast cancer 89% survival rate for localized breast](https://reader030.vdocument.in/reader030/viewer/2022040622/5d296e9d88c993f3778d3f98/html5/thumbnails/39.jpg)
Role of platelets in the early hours of metastatic colonization
Reference Labelle et al., PNAS, 2014
![Page 40: Biology of metastasis - Columbia University · Dispersion & seeding Detec/on and removal of primary tumor Treatments for primary breast cancer 89% survival rate for localized breast](https://reader030.vdocument.in/reader030/viewer/2022040622/5d296e9d88c993f3778d3f98/html5/thumbnails/40.jpg)
At the distant site (lung)
![Page 41: Biology of metastasis - Columbia University · Dispersion & seeding Detec/on and removal of primary tumor Treatments for primary breast cancer 89% survival rate for localized breast](https://reader030.vdocument.in/reader030/viewer/2022040622/5d296e9d88c993f3778d3f98/html5/thumbnails/41.jpg)
Role of VCAM1 in establishing lung metastasis
Chen and Massague, Clinical Cancer Research, 2012
![Page 42: Biology of metastasis - Columbia University · Dispersion & seeding Detec/on and removal of primary tumor Treatments for primary breast cancer 89% survival rate for localized breast](https://reader030.vdocument.in/reader030/viewer/2022040622/5d296e9d88c993f3778d3f98/html5/thumbnails/42.jpg)
Fighting for survival
![Page 43: Biology of metastasis - Columbia University · Dispersion & seeding Detec/on and removal of primary tumor Treatments for primary breast cancer 89% survival rate for localized breast](https://reader030.vdocument.in/reader030/viewer/2022040622/5d296e9d88c993f3778d3f98/html5/thumbnails/43.jpg)
Role of extracellular matrix molecules in metastasis
Tenascin C at the invasive edge of tumors
Ref: Oskarsson et al., Nature Medicine, 2011
![Page 44: Biology of metastasis - Columbia University · Dispersion & seeding Detec/on and removal of primary tumor Treatments for primary breast cancer 89% survival rate for localized breast](https://reader030.vdocument.in/reader030/viewer/2022040622/5d296e9d88c993f3778d3f98/html5/thumbnails/44.jpg)
Depleting Tenascin-C in cancer cells reduces lung metastasis
![Page 45: Biology of metastasis - Columbia University · Dispersion & seeding Detec/on and removal of primary tumor Treatments for primary breast cancer 89% survival rate for localized breast](https://reader030.vdocument.in/reader030/viewer/2022040622/5d296e9d88c993f3778d3f98/html5/thumbnails/45.jpg)
Role of Tnc in outgrowth of micrometastasis
TNC interaction with cancer cells at the invasive front enhances NOTCH and WNT signaling
Enhances fitness of metastasis Initiating cells
![Page 46: Biology of metastasis - Columbia University · Dispersion & seeding Detec/on and removal of primary tumor Treatments for primary breast cancer 89% survival rate for localized breast](https://reader030.vdocument.in/reader030/viewer/2022040622/5d296e9d88c993f3778d3f98/html5/thumbnails/46.jpg)
Extended survival of breast cancer cells for decades in the bone
ModifiedfromhAp://www.myxgeva.com/breast-cancer-bone-metastases.html
![Page 47: Biology of metastasis - Columbia University · Dispersion & seeding Detec/on and removal of primary tumor Treatments for primary breast cancer 89% survival rate for localized breast](https://reader030.vdocument.in/reader030/viewer/2022040622/5d296e9d88c993f3778d3f98/html5/thumbnails/47.jpg)
The undetectable but present Latent metastasis
![Page 48: Biology of metastasis - Columbia University · Dispersion & seeding Detec/on and removal of primary tumor Treatments for primary breast cancer 89% survival rate for localized breast](https://reader030.vdocument.in/reader030/viewer/2022040622/5d296e9d88c993f3778d3f98/html5/thumbnails/48.jpg)
Zhangetal.,CancerCell,Jul7,2009
![Page 49: Biology of metastasis - Columbia University · Dispersion & seeding Detec/on and removal of primary tumor Treatments for primary breast cancer 89% survival rate for localized breast](https://reader030.vdocument.in/reader030/viewer/2022040622/5d296e9d88c993f3778d3f98/html5/thumbnails/49.jpg)
Role of Src signaling in the survival of bone metastasis
• No role in homing to lungs or bone. • If these cells reach, then Src signaling becomes critical for their
outgrowth.
![Page 50: Biology of metastasis - Columbia University · Dispersion & seeding Detec/on and removal of primary tumor Treatments for primary breast cancer 89% survival rate for localized breast](https://reader030.vdocument.in/reader030/viewer/2022040622/5d296e9d88c993f3778d3f98/html5/thumbnails/50.jpg)
Src enhances survival and outgrowth of latent metastatic cells in the bone marrow
![Page 51: Biology of metastasis - Columbia University · Dispersion & seeding Detec/on and removal of primary tumor Treatments for primary breast cancer 89% survival rate for localized breast](https://reader030.vdocument.in/reader030/viewer/2022040622/5d296e9d88c993f3778d3f98/html5/thumbnails/51.jpg)
Brain metastasis from breast cancer
Modifiedfromwww.braintumors.in
![Page 52: Biology of metastasis - Columbia University · Dispersion & seeding Detec/on and removal of primary tumor Treatments for primary breast cancer 89% survival rate for localized breast](https://reader030.vdocument.in/reader030/viewer/2022040622/5d296e9d88c993f3778d3f98/html5/thumbnails/52.jpg)
Plasmin- reactive brain stroma for protection of host
Valienteetal.,Cell,2014
![Page 53: Biology of metastasis - Columbia University · Dispersion & seeding Detec/on and removal of primary tumor Treatments for primary breast cancer 89% survival rate for localized breast](https://reader030.vdocument.in/reader030/viewer/2022040622/5d296e9d88c993f3778d3f98/html5/thumbnails/53.jpg)
![Page 54: Biology of metastasis - Columbia University · Dispersion & seeding Detec/on and removal of primary tumor Treatments for primary breast cancer 89% survival rate for localized breast](https://reader030.vdocument.in/reader030/viewer/2022040622/5d296e9d88c993f3778d3f98/html5/thumbnails/54.jpg)
Joyce JA and Pollard JW, Nat Rev Cancer, 2009
Tumor microenvironment components
![Page 55: Biology of metastasis - Columbia University · Dispersion & seeding Detec/on and removal of primary tumor Treatments for primary breast cancer 89% survival rate for localized breast](https://reader030.vdocument.in/reader030/viewer/2022040622/5d296e9d88c993f3778d3f98/html5/thumbnails/55.jpg)
Macrophage/microglia microenvironment targeting in brain tumors
Pyonteck et al., Nat Med, 2013
![Page 56: Biology of metastasis - Columbia University · Dispersion & seeding Detec/on and removal of primary tumor Treatments for primary breast cancer 89% survival rate for localized breast](https://reader030.vdocument.in/reader030/viewer/2022040622/5d296e9d88c993f3778d3f98/html5/thumbnails/56.jpg)
T regulatory cells are present in growing tumors and metastases
Poor prognosis in breast cancers
![Page 57: Biology of metastasis - Columbia University · Dispersion & seeding Detec/on and removal of primary tumor Treatments for primary breast cancer 89% survival rate for localized breast](https://reader030.vdocument.in/reader030/viewer/2022040622/5d296e9d88c993f3778d3f98/html5/thumbnails/57.jpg)
Treg cells ablated from established tumors can reduce metastatic growth
![Page 58: Biology of metastasis - Columbia University · Dispersion & seeding Detec/on and removal of primary tumor Treatments for primary breast cancer 89% survival rate for localized breast](https://reader030.vdocument.in/reader030/viewer/2022040622/5d296e9d88c993f3778d3f98/html5/thumbnails/58.jpg)
Macrophage
Tum
or fa
ctor
s Tumor
Dendritic Cells
Neutrophil Eosinophil Basophil
Modified from Wynn, Nat Immunology, 14(3), 197-99
Myeloid derived suppressor cells in cancer - Another group of poor prognosis immunosuppressive cells
![Page 59: Biology of metastasis - Columbia University · Dispersion & seeding Detec/on and removal of primary tumor Treatments for primary breast cancer 89% survival rate for localized breast](https://reader030.vdocument.in/reader030/viewer/2022040622/5d296e9d88c993f3778d3f98/html5/thumbnails/59.jpg)
CXCL1/2 mediates mammary tumor progression
sh Control
shCXCL1/2 0
100
200
300
400
0 20 40
Tum
or v
ol. (
mm
3 )
p<0.
001
Days after injection
Tumor growth
0
20
40
Foci
num
ber/F
OV
shControl shCXCL1/2
p<0.0001
Lung
met
asta
sis shControl shCXCL1/2
Lung metastasis
shControl shCXCL1/2
Cle
aved
cas
pase
3
Apo
ptot
ic c
ells
/FO
V
0
10
20
30
shCon shCXCL1/2
* Apoptosis CXCR2
MMTV-PyMT MDA231-LM2
![Page 60: Biology of metastasis - Columbia University · Dispersion & seeding Detec/on and removal of primary tumor Treatments for primary breast cancer 89% survival rate for localized breast](https://reader030.vdocument.in/reader030/viewer/2022040622/5d296e9d88c993f3778d3f98/html5/thumbnails/60.jpg)
Granulocytic CD11b+Ly6G+ cells
CXCL1/2 recruit granulocytic CD11b+Ly6G+ cells in the tumor microenvironment
0 5 10 15
Unsorted
CD31+
CD11b+Gr1+
CD11b+Ly6C+
CD11b+Ly6G+
F4/80+
Cxcr2 mRNA levels (Relative units)
![Page 61: Biology of metastasis - Columbia University · Dispersion & seeding Detec/on and removal of primary tumor Treatments for primary breast cancer 89% survival rate for localized breast](https://reader030.vdocument.in/reader030/viewer/2022040622/5d296e9d88c993f3778d3f98/html5/thumbnails/61.jpg)
MDSC levels correlate with accelerated disease progression and poor survival in patients
- Breast Cancer (Diaz-Montero et al, 2009, Walter et al, 2012)
- Colorectal Cancer (Solito et al, 2011)
- Gastrointestinal Cancer (Gabitass et al., 2011)
- Lymphoma (Montero., 2012)
(Gabrilovich, Ostrand-Rosenberg and Bronte, 2012)
MDSC
Suppress Anti-tumor Immunity
Tumor Angiogenesis (Yang et al, 2004, Shojaei et al, 2007) Blood vessel remodelling and tumor cell extravasation (Yan et al, 2010)
![Page 62: Biology of metastasis - Columbia University · Dispersion & seeding Detec/on and removal of primary tumor Treatments for primary breast cancer 89% survival rate for localized breast](https://reader030.vdocument.in/reader030/viewer/2022040622/5d296e9d88c993f3778d3f98/html5/thumbnails/62.jpg)
0 20 40 60 80
100 120
0 20 40 60 Tum
or v
olum
e (m
m3 )
S100a9+/+bm S100a9-/- bm
p=0.
001
Days after injection
CXCL1/2 promotes tumor progression via myeloid cell S100A8/9
Met
asta
tic c
ells
/FO
V
S100a9-/- 0 2 4 6 8
10 12 14
p<0.0001
S100a9+/+
S100a9+/+ and S100a9-/- bone marrow reconstituted mice as recipients
Cancer cells to gland #4
Tumor growth Metastasis
Donor bone marrow
![Page 63: Biology of metastasis - Columbia University · Dispersion & seeding Detec/on and removal of primary tumor Treatments for primary breast cancer 89% survival rate for localized breast](https://reader030.vdocument.in/reader030/viewer/2022040622/5d296e9d88c993f3778d3f98/html5/thumbnails/63.jpg)
CXCL1/2
Breast primary
Metastasis Metasta/cstress
CXCL1/2
Cancer cell
CXCR2
CD11b+Gr1+MyeloidcellsSurvival
Survival
S100A8/9
S100A8/9
CXCL1/2 axis mediates tumor growth and metastasis
Invasionstress
![Page 64: Biology of metastasis - Columbia University · Dispersion & seeding Detec/on and removal of primary tumor Treatments for primary breast cancer 89% survival rate for localized breast](https://reader030.vdocument.in/reader030/viewer/2022040622/5d296e9d88c993f3778d3f98/html5/thumbnails/64.jpg)
Chemotherapy hyperactivates the CXCL1/2-S100A8/9 cycle
Neoadjuvant Rx samples
S10
0A8/
9 IH
C
scor
ing
Score 0 Score 1
Score 2 Score 3
S10
0A8/
9 sc
ore
Before chemo After chemo
p<0.0001
0
1 2
3 4
X
![Page 65: Biology of metastasis - Columbia University · Dispersion & seeding Detec/on and removal of primary tumor Treatments for primary breast cancer 89% survival rate for localized breast](https://reader030.vdocument.in/reader030/viewer/2022040622/5d296e9d88c993f3778d3f98/html5/thumbnails/65.jpg)
SB-265610
CXCR2 inhibitor enhances chemotherapy
Lung metastasis
Vehicle i-CXCR2 Two drugs
MD
A23
-LM
2 C
N34
-LM
1
AC chemo
Chemo
Met
asta
tic c
ells
/FO
V
CXCR2i +Chemo
0
4
8
12
16 MDA231-LM2
p=0.028
CN34-LM1
Chemo CXCR2i +Chemo
0
20
40
60
80 p=0.024 Days: 26
CXCR2 inhibitor
34 40 46 53 60
Chemo
0
Implant cancer cells
![Page 66: Biology of metastasis - Columbia University · Dispersion & seeding Detec/on and removal of primary tumor Treatments for primary breast cancer 89% survival rate for localized breast](https://reader030.vdocument.in/reader030/viewer/2022040622/5d296e9d88c993f3778d3f98/html5/thumbnails/66.jpg)
Primary tumor
Distant metastasis Brain
Bone
Vehicle chemo cxcr2i cxcr2i+chemo0
10000
20000
30000
40000Vehiclechemocxcr2icxcr2i+chemo
Nor
mal
ized
Pho
ton
Flux
Chemo Chemo+CXCR2i
Vehicle CXCR2i 0
10000
20000
30000
40000
![Page 67: Biology of metastasis - Columbia University · Dispersion & seeding Detec/on and removal of primary tumor Treatments for primary breast cancer 89% survival rate for localized breast](https://reader030.vdocument.in/reader030/viewer/2022040622/5d296e9d88c993f3778d3f98/html5/thumbnails/67.jpg)
Cytotoxic chemo, shortlived targeted therapy…..immunotherapy promise
hAp://www.revealtherapies.com/AllPages/Immunotherapy.html
![Page 68: Biology of metastasis - Columbia University · Dispersion & seeding Detec/on and removal of primary tumor Treatments for primary breast cancer 89% survival rate for localized breast](https://reader030.vdocument.in/reader030/viewer/2022040622/5d296e9d88c993f3778d3f98/html5/thumbnails/68.jpg)
Dispersion&seedingDetec/onandremoval
ofprimarytumor
Treatments for primary breast cancer
89%survivalrateforlocalizedbreastcancers