Invasion and MetastasisDr Wirsma Arif HarahapSurgical Oncologist

Benign tumors generally do not spread by invasion or metastasisMalignant tumors are capable of spreading by invasion and metastasis Malignant versus Benign Tumors

1. Biology of tumor growth2. Tumor angiogenesis3. Tumor progression and heterogeneity4. Cancer Cells and Microeviroment5. Tumor spreadOBJECTIVE

1. Biology of tumor growth2. Tumor angiogenesis3. Tumor progression and heterogeneity4. Cancer Cells and Microeviroment5. Tumor spread (mnjalar)OBJECTIVE

1. Biology of tumor growth

The natural history of malignant tumors can be divided into four phase:

A. Transformation B. Growth of transformation cells C. Local invasion D. Distant metastases

Tumor growth

(a) Rate of growth

Benign: slowly years to decades

Malignant: rapidly moths to years

(b) Pattern of growth

Expansile a. Well-demarcated (pmbtasan) and encapsulated b. Gradually (berangsur) c. Surgically enucleated easely. d. The particular growth pattern of benign tumors

Expansile Growth pattern

Invasive

a. Progressive infiltration, invasion, and destruction of the surrounding tissue

b. Ill-defined (tegas) and non-encapsuled

c. The particular growth pattern of malignant tumors

d. Be surgically enucleated difficultly

Invasive growth pattern

Exospheric

a. Tumors growth projecting on the surface, booty cavities, or the lumen

b. Commonly polyp, mushroom, and finger-like

c. Growth pattern of both benign and malignant tumors

Exospheric growth pattern

1. Biology of tumor growth2. Tumor angiogenesis3. Tumor progression and heterogeneity4. Cancer Cells and Microeviroment5. Tumor spreadOBJECTIVE

(2) Tumor angiogenesis Angiogenesis is necessary for biologic correlate of malignancy.

Development cancer > 1mm hypoxia cell cancer release hif ( hipoxia inducing factor ) endothel release VEGF ( vascular endothelial growth fctr)

VEGF angiogenesis

*Tumor Angiogenesis

*Tumor Angiogenesis

Angiogenesis is required for tumors to grow beyond a few millimeters in diameterIn 1971, Judah Folkman, signal molecules for new blood vessel formationTumor angiogenesis The processes of cancer cells stimulate the development of a blood supply

*Tumor Angiogenesis

1. Biology of tumor growth2. Tumor angiogenesis3. Tumor progression and heterogeneity4. Cancer Cells and Microeviroment5. Tumor spreadOBJECTIVE

(3) Tumor progression and heterogeneityDespite (meskipun) most malignant tumors are monoclonal in origin, by the time they become clinically evident, their constituent (unsur pokok) cells are extremely heterogeneous resulting from multiple mutations that accumulate independently in different cells.

1. Biology of tumor growth2. Tumor angiogenesis3. Tumor progression and heterogeneity4. Cancer Cells and Microeviroment5. Tumor spreadOBJECTIVE

4. Cancer Cells and MicroeviromentCancer cells cannot growth by itselfIt is need support by microenviroment (stromal). (lingkungan pd tngkat selular)Lack of supporting cancer cells will die.

Tumor Cells

-Epithelial

-Mesenchymal

-HematopoieticMicroenvironment

-Fibroblasts/Myofibroblasts

Endothelial Cells

Myoepithelial Cells

Leukocytes

-Extracellular Matrix

Usually Bulk of Tumor

Bi-directional Interactions between Cancer cells and enviromentMicroenvironment can contribute positive or negative signals to tumor cells: signalsmay be mediated by bioactive productsor cell-cell contact

Tumor cells modify the microenvironment to produce bioactive products such as growth factors, chemokines, matrix-degrading enzymes that enhance (memperbsar) the proliferation,survival, invasion, and metastasis of tumor cells.

Crosstalk Between Tumor Cells and Microenvironment Mueller and Fusenig, 2004

1. Biology of tumor growth2. Tumor angiogenesis3. Tumor progression and heterogeneity4. Cancer Cells and Microeviroment5. Tumor spreadOBJECTIVE

5. Tumor spread

The spread is a cheracteristic of malignant tumors

(1) Local invasion(2) Metastasis

The steps and mechanism of invasion :

i. Cancerous cells attaching basement membrane. ii. Local proteolysis iii. Locomotion Cancers cells invade, penetrate local tissue fissure (celah) progressively. 1. Local Invasion

The three steps of invasionLiotta, LA. Tumor invasion and metastasis-role of the extracellular matrix. Cancer Res 46: (1986)1Matrix attachment2Matrix degradationLocomotion3

How do cells move through tissues?Acquire invasive abilityAbility to degrade extracellular matrix (ECM)Acquire motile abilityLose cell-cell junctions (EMT-like switch)Acquire motile capabilityDirected migration to hospitable sitesChemotaxisCommunication between tumor and host cells

*Cell motility activationBy signal moleculesFrom cancer cells or surrounding cellsProteases productionTo remove cancer cell movement barriersPlasminogen activator (plasminogen plasmin) (fig. 3-9)

How do cells move through tissues?Cont..

*Invasion and Metastasis

Matrix degradation by proteinasesMetalloproteinases (MMPs)Serine proteinases (plasmin, uPA)Cysteine proteinase (Cathepsin B,L)Aspartyl proteinases (Cathepsin D)Threonine proteinases (not extracellular)

(2) Metastasis

Definition: metastasis connotes (berarti) the development of secondary implants discontinuous with the primary tumor, possibly in remote tissue.

*Distant Metastasis

Cancer Cells Follow The blood streamGrowth in anotherOrgan

Invasion and Metastasis

Figure 14.4 The Biology of Cancer ( Garland Science 2007) p. 591Invasion-Metastasis Cascade Adapted from Fidler, Nat. Rev. Cancer 3: 453-458, 2003

Colon Carcinoma Metastatic to LiverBreast Carcinoma Metastatic to BrainFig. 2.2b and cWeinbergp. 27

Organ-specific factors play a role in determining where cancer cells will metastasizeSeed (bbit) and soil (tanah) hypothesisOnly a few sites provide an optimal environment for the growth for a particular type of cancer cellThe ability of cancer cells to grow in different locations is affected by interactions between cancer cells and molecules present in the specific organs

Lymphatic metastasis a. This is the most common pathway for initial dissemination (pnyebaran) of carcinoma.

b. Tumor cells gain (peroleh) access to an afferent lymphatic channel and carried to the regional lymph nodes.

In lymph nodes, initially tumor cell are confined (mngurung) to the subcapsular sinus; with the time, the architecture of the nodes may be entirely destroyed and replaced by tumor.

c. Through the efferent lymphatic channels tumor may still be carried to distanced lymph rode, and enter the bloodstream by the way of the thoracic duct finally.

d. Destruction of the capsule or infiltration to neighboring lymph nodes eventually causes these nodes to become firm (tegas), enlarged and matted together.

Metastasis via LymphaticsLymphatic Drainage of the Breast

Metastasis via LymphaticsIdentification of Sentinel Lymph Node with Dye

Metastasis via LymphaticsH&E Staining: Breast Ca in Lymph Node

Metastasis via LymphaticsKeratin Staining: Breast Ca in Lymph Node

Hematogenous metastasis

a. This pathway is typical of sarcoma but is also used by carcinoma b. Process: tumor cells small blood vessels tumor emboli distant parts adheres to the endothelium of the vessel invasive the wall of the vessel proliferate in the adjacent (brdkatan/brbtsan) tissue establish a new metastatic tumor.

c. follow the direction of blood flow. Tumors entering the superior or inferior vena cava will be carried to the lungs tumors entering the portal system will metastasize to the liver. d. Some cancers have preferential (istmwa) sites for metastases lung cancer offal metastasize to the brain, bones, and adrenal glands. Prostate cancer frequently metastasize to the bones. e. Morphologic features of metastasis tumors multiple, circle, scatter (mnyebar)

Implantation metastasis

a. Tumor cells seed the surface of body cavities b. Most often involved is the peritoneal cavity c. But also may affect pleural, pericardial, subarachnoid, and joint space.

Mechanisms of invasion and metastasis

Invasion of the extracellular metastasis

a. Loosening up of tumor cells from each other: E-adhering expression is reducedb. Attachment to matrix components: cancer cells have many more receptors of lamina and fibronectin. (glikoprot adesif permukaan)c. Degradation of extra cellular matrix:Tumor cells can secrete proteolytic enzymes or induce host cells to elaborate proteases.

Vascular dissemination and homing of tumor cellsa. Tumor cells may also express adhesion molecules whose ligands are expressed preferentially on the endothelial cells of target organ.b. Some target organs may liberate (membebaskan) chmoattractonts that tend (cndrung) to recruit tumor cells to the site. e. g. insulin-like growth factor , .c. In some cases, the target tissue may be not an permissive environment. i. g. inhibitors of proteases could prevent the establishment of mend of a tumor cottony.

Molecular genetics of metastases At present, no single metastasis gene has been found, just son conciliates

a. High expression of nm23 gene often accompanied with low metastatic potential. b. KAI-I gene, located on 11pn-2, expressed in normal prostate but not in metastasis prostate cancer.c. KISS gene, also located on human chromosome , analogous manner (cara) in human malignant melanoma.

(Quoted fromRobbins PathologyBasis of disease)

Figure 14.42 The Biology of Cancer ( Garland Science 2007)p. 635Primary Tumors and Preferred Sites of Metastatic Spread

Presence of Micrometastases and Clinical Prognosis: Colon CancerFigure 14.50b The Biology of Cancer ( Garland Science 2007)p. 645

Factors Hindering Metastatic SpreadMetastasis-Suppressor Genes: e.g. - TIMP: Tissue Inhibitor of Metalloproteinases - CAD1 gene: for E-cadherin

2. Host Responses Activated MacrophagesNatural Killer CellsCytotoxic Lymphocytes

3. Hydrodynamic Effects in Host circulation

4. Failure to Recognize and Arrest at Secondary Site

StopMets

*Specific genes promote or suppress the ability of cancer cells to metastasizeMatrix metalloproteinases (MMPs) inhibitors can inhibit cancer cells metastasisMetastasis promoting genesMMPs cancer cellsEnhancement (pningktn) of metastasis promoting genesDiminishing of metastasis suppressor genes

Routes of tumor spread Hematogenous (bloodstream)sarcomas, carcinomas, leukemias

Lymphatic (lymph nodes)carcinomas

Direct extension (surface implantation, ascites) ovarian, other carcinomas

Organ site preference for metastasisColon adenocarinomaLiverBreast adenocarcinomaBone, brain, adrenalProstate adenocarcinomaBoneLung: SCLCBone, brain, liverMelanoma - cutaneousBrain, liver, colonThyroid adenocarcinomaBoneKidney clear cell carcinomaBone, liver, thyroidTestis carcinomaLiverBladder carcinomaBrainNeuroblastomaLiver, adrenalLung and liver: common sites of metastasis

*Depending on whether or not they can spread by invasion and metastasis, tumors are classified as being either benign or malignant. Benign tumors are tumors that cannot spread by invasion or metastasis; hence, they only grow locally. Malignant tumors are tumors that are capable of spreading by invasion and metastasis. By definition, the term "cancer" applies only to malignant tumors.