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.

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Distant Loco-regional

Contra-lateral

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12

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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