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Molecular Mechanism of Molecular Mechanism of Distant Metastasis Distant Metastasis
and Clinical Implicationand Clinical Implication
ศาสตราจารยศาสตราจารย ดรดร..นพนพ.. พรชยัพรชยั โอเจรญิรตันโอเจรญิรตัน
สาขาวิชาศลัยศาสตรศรีษะสาขาวิชาศลัยศาสตรศรีษะ--คอและเตานมคอและเตานมภาควิชาศลัยศาสตรภาควิชาศลัยศาสตร
คณะคณะแพทยแพทยศาสตรศาสตรศริิศริิราชพยาบาลราชพยาบาล
Avastin, Erbitux, Gleevec, Herceptin…
The new wonder drugs might make you think
we’re finally beating this dreaded scourge
We’re not
“Failure to control establishment of secondary colonies was the major contributor to failure…
Winning the war against cancer would require increasing resources devoted to studying metastasis”
What is the Importance of What is the Importance of Distant Metastasis?Distant Metastasis?
Metastasis is the Cause of Metastasis is the Cause of 90% of Deaths from Breast Cancer90% of Deaths from Breast Cancer
Distant Recurrences are AssociatedDistant Recurrences are Associatedwith the Highest Risk of Deathwith the Highest Risk of Death
* Hazard ratio (and P value) relative to patients with no recurrence.J Clin Oncol. 2005;23(16S):62s. Abstract 738.
Rel
ativ
e ris
k of
dea
th (H
R)* P<0.001
P<0.001P=0.01
Distant Loco-regional
Contra-lateral
0
2
4
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Molecular Mechanism of Molecular Mechanism of Distant MetastasisDistant Metastasis
The "The "HalstedianHalstedian" Theory" Theory
“Breast cancer begins as a strictly LOCALdisease and that tumor cells spread over time in
a contiguous manner away from the primary site
through lymphatics.
Distant metastases are the result of direct
extensions of local involvement.”
Halsted WS. Ann Surg 1907; 46: 1-19
“Breast cancer is a SYSTEMIC disease and can be divided into two distinct groups: tumors that have the ability to metastasize and those that lack this ability.
If distant metastases were destined to develop, such metastases had already occurred at the time of diagnosis of the breast tumor. ”
Fisher B. Cancer 1977; 40: Suppl 1: 574-87
The The ““Systemic" TheorySystemic" Theory
“Breast cancer is a heterogeneous disease . . . [with] a spectrum extending from a disease that remains local throughout its course to one that is systemic when first detectable.
Failure to achieve initial local control will allow SOME tumors to disseminate later to distant sites.”
Hellman S. J Clin Oncol 1994; 12: 2229-34
The The ““Spectrum" TheorySpectrum" Theory
Models of the Metastatic CascadeModels of the Metastatic Cascade
Nat Rev Cancer 2004; 4: 448-56
PPotentialotential RRoutesoutes of of Distant MDistant Metastasisetastasis
Ann NY Acad Sci 2008; 1131: 225-34
Molecular Mechanism of Molecular Mechanism of Lymph Node MetastasisLymph Node Metastasis
Lymph Node Metastasis Lymph Node Metastasis Extent of lymph node metastasis is a major determinant for staging, prognosis and therapeutic decisions in most solid tumors
During the intial stages of the metastasis,there is a strong predilection for spread to regional lymph nodes
Molecular Biology of Lymphatic System Molecular Biology of Lymphatic System
Sentinel LSentinel Lymphymph NNode ode in Breast Cancerin Breast Cancer
Mechanism of Mechanism of Lymph Node Metastasis Lymph Node Metastasis
Traditional View
Tumor cells are passively taken up by lymphatic
vessels along with interstitial fluid and are
facilitated by higher permeability of lymphatic
vessels and absence of basement membrane
barrier
Current View
1. Suppression of anti-tumor immunoresponses
2. Induction of lymphangiogenesis
3. Preparing metastatic niche
Mechanism of Mechanism of Lymph Node Metastasis Lymph Node Metastasis
“The first lymphoid organ to respond to tumor antigenic stimulation”
Cancer cells produce immunomodulators that lead to immunosuppression and reduction of the density and maturity of dendritic cells and T-cells in SLN
Primary tumors enable suppression of the immune functions and facilitate development of SLN metastasis
Suppressed Suppressed ImmunoresponsesImmunoresponsesin SLN against Tumor Metastasisin SLN against Tumor Metastasis
LLymphangiogenesisymphangiogenesis in in Tumor & SLNTumor & SLN
Tumor lymphangiogenesis significantly predicted
the presence of SLN metastases
Lymphangiogenic growth factors secreted from a
primary tumor induce lymphangiogenesis in SLN
before metastasizing to these tissues
“Tumor-reactive lymphadenopathy”
Lymphangiogenesis in metastasis-containing SLN
facilitates further metastatic spread
LymphangiogenicLymphangiogenic Factors Factors
VEGFVEGF--A and VEGFA and VEGF--CCPredict Nodal MetastasisPredict Nodal Metastasis
O-charoenrat P, et al. Cancer 2001;92:556–68
The Importance of The Importance of Lymphangiogenesis in Breast CancerLymphangiogenesis in Breast Cancer
Intra- and peri-tumoral lymphatic vessels are important for promoting lymphatic metastasis
Increased levels of VEGF-C promote tumor and SLN lymphangiogenesis, regional nodal spread and distant metastasis
VEGF-A induces tumor and SLN lymphangiogenesis and promotes lymphatic metastasis
Cancer Res 2001; 61: 1786–90; Int J Caner 2002; 98: 946–51J Exp Med 2005; 201: 1089–99; Blood 2007; 109: 1010-7
VEGFVEGF--C Increases Metastasis by Increasing C Increases Metastasis by Increasing Delivery of Cancer Cells to Lymph NodesDelivery of Cancer Cells to Lymph Nodes
Cancer Res 2006; 66: 8065-75
Lancet Oncol 2002; 3: 44–52
LLymphangiogenesisymphangiogenesis in in Sentinel LSentinel Lymphymph NNodeode
ChemokinesChemokines and and Lymphatic MetastasisLymphatic MetastasisSmall secreted proteins that regulate the chemotacticresponse
SLN produce and release specific chemokines that attract cancer cells bearing specific corresponding receptors in primary sites
CXCR4 and CXCR7 were highly expressed in breastcancer, and their ligand CXCL12/SDF-1 was expressed in bone marrow, lung, and LN where breast cancer cells preferentially metastasize
Nature 2001; 410: 50–6
Seed and Soil HypothesisSeed and Soil Hypothesis
“When a plant goes to seed, its seeds are carried in all directions; but they can only grow if they fall on congenial soil.”
Stephen Paget, 1889
Priming the Priming the ‘‘Soil' for Cancer MetastasisSoil' for Cancer Metastasis::The PreThe Pre--metastatic Nichemetastatic Niche
Lymphagiogenesis
Molecular Mechanisms of Molecular Mechanisms of SLN MetastasisSLN Metastasis
Cancer Metastasis Rev 2006; 25:677–94
Lymphangiogenesis in Breast Cancer:Lymphangiogenesis in Breast Cancer:Clinical ImplicationClinical Implication
Clinical ImplicationClinical ImplicationPrognostic markers - Monitoring the abundance of lymphatics in oradjacent to a primary tumor or SLN
- Analyzing expression of lymphangiogenic growthfactors and their cognate receptors
Therapeutic implications- Targeting VEGFR-3 and/or VEGFR-2 pathway,chemokine receptors CXCL12-CXCR4 signaling(antibodies, small molecule kinase inhibitors)
Targeting Targeting LymphagiogenicLymphagiogenic PathwayPathway
Clin Exp Metastasis 2007; 24:619–36
Targeting Lymphangiogenesis to Targeting Lymphangiogenesis to Prevent Tumor MetastasisPrevent Tumor Metastasis
SunitinibSunitinib: Mechanism of Action : Mechanism of Action
Inhibition of cancer progression & metastasis
↑ VEGF ↑ PDGF
Lymphaticpermeability
Cell survival, proliferation, migration
Lymphaticformation, maturation
VEGFR PDGFRVEGFVEGF PDGFPDGF
Lymphatic Endothelial CellLymphatic Endothelial Cell Pericyte/Fibroblast/Vascular Smooth Muscle
Pericyte/Fibroblast/Vascular Smooth Muscle
SunitinibSunitinibSunitinib
Clin Cancer Res; 9:327-337, 2003
MultiMulti--kinasekinase Inhibitors Inhibitors
No ongoing phase III trialsFour ongoing phase III trials in MBCSun + paclitaxel versus Avastin + paclitaxel, sun +
docetaxel versus docetaxel, sun versus Xeloda,sun + Xeloda versus Xeloda
Seven ongoing phase II trialsFour first-line MBC
Sor + endocrine therapy versus endocrine therapy
Sor + paclitaxel versus paclitaxelSor + nab-paclitaxel
Three second-/third-line MBCMonotherapy x 2Sor + gemcitabine versus gemcitabine
Eight ongoing phase II trialsTwo neoadjuvant:
Monotherapy, sun + weekly paclitaxel ACThree MBC first-line
Monotherapy, sun + Avastin + paclitaxel,Sun + Herceptin
Three MBC second-/third-lineMonotherapy x 2,Sun versus standard of care in triple-negativebreast cancer
Phase II second-line monotherapy trial in MBC (n=54)2
PR = 1.9%, SD >6 months = 11%
Phase II monotherapy trial in MBC (n=64)1
PR = 14%, SD >6 months = 5%
Sorafenib (sor)Sunitinib (sun)
1Miller KD, et al. Oral presentation at ASCO 2007 (Abstract 563)2Bianchi GV, et al. Poster presentation at ASCO 2007 (Abstract 164)
Metastatic spread is the most lethal aspect of cancer and often occurs via lymphatic vasculature
The immune suppression in SLN by tumor cells results in failure of prevention or eradication of tumor metastasis
Lymphangiogenic growth factors promote formation of tumor lymphatics and metastatic spread of tumor cells to lymph nodes
ConclusionConclusion
‘Chemokine-chemokine receptor network’ plays an important role in lymphatic metastasis
Lymph node lymphangiogenesis may contribute to further metastatic tumor spread beyond the SLN
Efficient anti-lymphangiogenic therapies are needed
ConclusionConclusion
Thank you for your attentionThank you for your attention
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