1.The metastatic cascade. 2.Pathologic features of metastasis. 3.Therapeutic ramifications

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1 Metastasis 1.The metastatic cascade 2.Pathologic features of metastasis 3.Therapeutic ramifications

2 Sir James Paget ( ) British Surgeon/ Pathologist Paget s disease of bone Paget s disease of the nipple (intraduc- tal Ca breast spreading to skin of nipple)

3 Stephen Paget, MD ( ) METASTASIS: Seed and Soil Paget S. The distribution of secondary growths in cancer of the breast. Lancet 1889; 1: the best work in pathology of cancer is done by those who are studying the nature of the seed the observations of the properties of the soil may also be useful.

4 liver Carcinoma of fbreast

5 Which malignant cells will metastasize? 1. Subclone theory 2. Cancer stem cell theory -a specific clone has the prop s p for metastasis -only the stem cells have the prop s for metastasis 3. Genetic signature theory -many malignant cells at different stages have the signature genes allowing metastasis 70-gene signature for mets in breast Ca

6 TUM TUM epithelium B.M.: laminin + coll. IV ECM lungs bone brain lymph nodes liver distant sites blood vessels: cap./venule/lymphatic

7 1. Invasion of B.M. & ECM TUM TUM epithelium B.M.: laminin + coll. IV ECM lungs 3. Extravasation, colonization & growth bone brain lymph nodes distant sites liver 2. Intravasation & vasc. disseminationi blood vessels: cap./venule/lymphatic

8 Stage 1: Invasion of B.M. and ECM TUM TUM epithelium B.M.: laminin + coll. IV ECM lungs E-cadherin bone brain liver 1. Loosening lymph of tumor cells nodes blood vessels: cap./venule/lymphatic E-cadherin distant sites Mutation of E-cadherin Inappropriate expression of SNAIL & TWIST (which hregulate E-cadh. expres.) (Secondary effect: E-cadherin normally sequesters ß-catenin cell proliferator so with less sequestered, more tumor cells proliferate)

9 2. Degradation of B.M. & ECM TUM TUM epithelium B.M.: laminin + coll. IV ECM MMP s (esp. MMP9: gelatinase action on b.m. type IV collagen) Cathepsin i D Urokinase plasminogen activator Type IV collagenase blood vessels: cap./venule/lymphatic

10 integrin with affinity for laminin and other ECM proteins 3. Change in attachment t of tumor cells to ECM proteins

11 EMT: epithelial- mesenchymal transition ECM ECM vimentin SMA (smooth muscle actin) 4. Locomotion of tumor cells

12 Stage 2: Intravasation & vasc. dissemination TUM TUM epithelium B.M.: laminin + coll. IV Vessel size Shear stress ECM NK cell mac platelet-tumortumor emboli Up-regulate adh. molecules for endothel. TNF-α IFN-γγ HOSTILE ENVIRONMENT: Most tumor cells do not survive

13 Stage 3: Extravasation, colonization & growth lungs bone Angiogenesis EMT Chemokine express. Adhesion i molecules l Down-regulate metastasis t suppressor proteins brain lymph nodes liver blood vessels: cap./venule/lymphatic

14 Alveolar space Example: METASTASIS TO LUNG

15 Alveolar space Vascular Sprouting Example: METASTASIS TO LUNG

16 Angiopoietins 1 & 2 pericyte Ang-1 TIE-2 receptor VEGFR hypoxia HIF-1α TGF-α, ß PDGF FGF EGF angiogenin (hypoxia inducible factor) VEGF ABDE: A,B,D,E: angiogenesis endothelial mitosis A-B-C-D-E lymphangiogenesis

17 TUM TUM TUM Anti-angiogenic factors thrombospondin-1 p53 expression VEGF expression Proteases (from tumor cells or proteolytic from stromal cells): cleavage Plasminogen angiostatin Collagen endostain Transthyretin vasculostatin

18 liverliver Carcinoma of fbreast

19

20 Chemokine receptors on tumor Cells: ligands in metastatic sites CXCR7 CXCL21 N Engl J Med 2001; 345:

21 Breast Carcinoma (invasive)

22 intraductal carcinoma fibrosis (desmoplasia) invasive i Ca necrosis lymphatic Breast Carcinoma (intraductal and invasive)

23 Ductal carcinoma In situ (DCIS)

24

25 invasion B.M. BM

26 Intraductal and invasive Carcinoma

27

28

29 Lymph node lymphatic

30 capsule subcapsular sinus

31

32 Blood vessels inflammation i Ingrowth of Ingrowth of fibroblasts & stroma

33 General Modes of Metastasis carcinoma lymphatics regional lymph nodes sarcoma veins lungs bone

34 Common Sites of Metastasis Colorectal Breast Renal cell Ca Hepatocellular Ca ColorectalC l t l Pancreas Other GI: carcinoid, bile ducts LungL Breast Lung Liver

35 Common Sites of Metastasis Breast Prostate Renal cell Ca Bone Lung Breast Melanoma Renal cell Ca Brain Neuroaxis Vert. veins

36 Unique Sites of Metastasis Virchow s node (supraclavicular node) gastric Ca (signet ring Ca) Krukenberg tumor (bilateral ovarian mets)

37 Lung Carcinoma metastasis to Adrenal Source: University of Alberta, Dep t of Laboratory Medicine & Pathology

38 Therapeutic Implications

39 TUM TUM epithelium B.M.: laminin + coll. IV ECM lungs bone brain lymph nodes liver distant sites blood vessels: cap./venule/lymphatic

40 Anti-angiogenic agents Agent Mech. of action Neoplasm(s) Monoclonal Ab Bevacizumab against VEGF colorectal Sunitinib Sorafenib Multi-kinase inhibitor of VEGFR, PDGFR renal cell; GIST Multi-kinase inhibitor: VEGFR, PDGFR, C-kit, Raf renal cell Anti-chemokine receptors

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