1. The metastatic cascade. 3. Pathologic features of metastasis. 4. Therapeutic ramifications. Which malignant cells will metastasize?

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1 1. The metastatic cascade 3. Pathologic features of metastasis 4. Therapeutic ramifications Sir James Paget ( ) British Surgeon/ Pathologist Paget s disease of Paget s disease of the nipple (intraductal Ca breast spreading to skin of nipple) 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. Carcinoma of breast Which malignant cells will metastasize? 1. Subclone theory 2. Cancer stem cell theory -a specific clone has the prop s for metastasis brain distant sites -only the stem cells have the prop s for metastasis 3. Genetic signature theory 70-gene signature for mets in breast Ca -many malignant cells at different stages have the signature genes allowing metastasis 1

2 3. Extravasation, 1. Invasion of B.M. & colonization & growth brain 2. Intravasation & vasc. dissemination distant sites Stage 1: Invasion of B.M. and E-cadherin brain 1. Loosening of tumor cells E-cadherin distant sites Mutation of E-cadherin Inappropriate expression of SNAIL & TWIST (which regulate E-cadh. expres.) blood (Secondary vessels: cap./venule/atic effect: E-cadherin normally sequesters ß-catenin cell proliferator so with less sequestered, more tumor cells proliferate) 2. Degradation of B.M. & MMP s (esp. MMP9: gelatinase action on b.m. type IV collagen) Cathepsin D Urokinase plasminogen activator Type IV collagenase integrin with affinity for laminin and other proteins 3. Change in attachment of tumor cells to proteins vimentin EMT: epithelialmesenchymal transition SMA (smooth muscle actin) Stage 2: Intravasation & vasc. dissemination Vessel size Shear stress NK cell mac platelet-tumor emboli Up-regulate adh. molecules for endothel. TNF-α IFN-γ 4. Locomotion of tumor cells HOSTILE ENVIRONMENT: Most tumor cells do not survive 2

3 Stage 3: Extravasation, colonization & growth brain Angiogenesis EMT Chemokine express. Adhesion molecules Down-regulate metastasis suppressor proteins Alveolar space Example: METASTASIS TO LUNG Angiopoietins 1 & 2 Ang-1 TIE-2 receptor Alveolar space TGF-α, ß PDGF FGF EGF angiogenin hypoxia Vascular Sprouting pericyte HIF-1α VEGFR (hypoxia inducible factor) VEGF Example: METASTASIS TO LUNG A-B-C-D-E A,B,D,E: angiogenesis angiogenesis endothelial mitosis Anti-angiogenic factors thrombospondin-1 p53 expression VEGF expression Proteases (from tumor cells or from stromal cells): proteolytic cleavage Plasminogen angiostatin Collagen endostain Transthyretin vasculostatin Carcinoma of breast 3

4 Chemokine receptors on tumor Cells: ligands in metastatic sites CXCL21 CXCR7 N Engl J Med 2001; 345: intraductal carcinoma fibrosis (desmoplasia) invasive Ca necrosis atic Breast Carcinoma (invasive) Breast Carcinoma (intraductal and invasive) Ductal carcinoma In situ (DCIS) 4

5 invasion B.M. Intraductal and invasive Carcinoma Lymph node atic capsule subcapsular sinus 5

6 Blood vessels inflammation Ingrowth of fibroblasts & stroma Common Sites of Metastasis General Modes of Metastasis carcinoma atics regional veins Colorectal Pancreas Other GI: carcinoid, bile ducts Lung sarcoma Colorectal Renal cell Ca Hepatocellular Ca Common Sites of Metastasis Lung Liver Unique Sites of Metastasis Prostate Renal cell Ca Virchow s node (supraclavicular node) Bone Lung Melanoma Renal cell Ca Vert. veins Brain Neuroaxis gastric Ca (signet ring Ca) Krukenberg tumor (bilateral ovarian mets) 6

7 Lung Carcinoma metastasis to Adrenal Source: University of Alberta, Dep t of Laboratory Medicine & Pathology brain distant sites Anti-angiogenic agents Agent Mech. of action Neoplasm(s) Bevacizumab against VEGF colorectal Sunitinib Sorafenib Monoclonal Ab Multi-kinase inhibitor of VEGFR, PDGFR renal cell; GIST Multi-kinase inhibitor: VEGFR, PDGFR, C-kit, Raf Anti-chemokine receptors renal cell 7