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CCB Exam 3
Terms in this set (48)
blood and lymph vessel
Most tumors are able to attract blood vessels initially
At some point during tumor progression, some pre-neoplastic cells acquire the ability to provoke neoangiogenesis
As tumors grow, the resulting hypoxia triggers p53-dependent apoptosis
The change in the behavior of these small tumor masses is called "angiogenic switch", a minor step in tumor
Tumor microvessel characteristics
Tumors have haphazardly constructed microvessels. They contain gaps in between their wall seems, have highly irregular chaotic network structure, have significant leakage, have a reduced amount of lymphatic vessel and their drainage is defected
Pericytes are smooth muscle cells that help stabilize capillary walls and control permeability
Loose attachment of pericytes result in capillary leakage
Following angiogenic switch, a dramatic induction of vessel formation promotes tumor growth.
Normal islet cells are poorly vascularized and is sustained largely through diffusion from the microvessels surrounding it.
The angiogenic switch depends on the recruitment of inflammatory cells, mast cells and macrophages
Angiogenic switching occurs in VEGF-deficient Rip-Tag mice.
Activation of VEGFs by MMP-9
1. RIP-Tag mice engineered to lack Kit receptor (for Stem Cell Factor, SCF) develop hyperplastic islets that never succeed in becoming tumors.
2. However, a bone marrow transplant with wild-type cells leads malignant tumor formation since the mast cells now respond, become activated and induce angiogenesis via their production of MMP9.
3. Bone-marrow derived infiltrating immune cells are essential for tumor neo-angiogenesis
Advanced human tumors often produce a complex mixture of multiple angiogenic factors. Anti-angiogenic therapy thus becomes complicated in such cases.
Angiogenesis and invasiveness are loosely coupled
Acquisition of invasiveness leads to more intense neo-angiogenesis and increased density of capillaries
Patients whose tumors have a higher microvessel count have a higher probability of survival
Patients whose tumors express VEGF have a higher probability of survival
Tumors overexpressing TSP-1 (Thrombospondin 1) typically grow faster, exhibit more angiogenesis, and have more metastases
p53 can induce the transcription of TSP1 gene while
Ras causes shutdown of TSP1 gene.
The stimulation of resting endothelial cells with angiogenic agents, such as VEGF or bFGF, creates activated, growing endothelial cells, which soon express the Fas death receptor on their surface
Treatment of mature and recently formed endothelial cells with thrombospondin-1 (Tsp-1) causes both groups of cells to secrete FasL, the ligand of Fas
Only activated endothelial cells display the Fas receptor and are further induced to enter into apoptosis by Tsp-1
Tsp-1 can block new angiogenesis and on already- constructed vasculature, whose endothelial cells are only rarely involved in active proliferation
The FasL secreted by the mature, resting endothelial cell can be induced to enter apoptosis because its able to bind and respond to secreted FasL
Activators of the angiogenic switch: VEGF, FGF 1,2
Inhibitors of the angiogenic switch: IFN a/b, Thrombospondin 1/2
Basement membrane extracellular matrix
Inhibitors of matrix turnover, matrix degrading enzymes, integrin
Neutrophil macrophage mast cell
anti inflammatory inhibitors, cytokine and chemokine inhibitors, NFkB, IKK, TNFa inhibitors
anti lymphatic targeting, inhibitors of VEGF or PDGF
Inhibitor of PDGF signaling,
inhibitors of VEGF, endogenous angiogenesis inhibitors
The microenvironment is a network of scaﬀolding made out of collagens, glycoproteins, growth factors, and glycans coupled with the cellular component comprising the normal stromal elements, fibroblasts, endothelial cells, and immune cells into which the tumor cells invade and grow.
The scaﬀolding materials form structures, such as the basement membrane surrounding epithelial and endothelial structures, that separate tissue compartments
Tumor cells penetrate the basement membrane to enter the underlying interstitial stroma during a transition from invasive to in-situ carcinoma.
The process of invasive behavior and the phenotypic and genotypic changes associated with it is often called mesenchymal-epithelial transition involving the transforming growth factor-β/ SMAD family of cytokines.
Loss of continuity of the basement membrane, the dense meshwork of type IV collagen, glycoproteins, such as laminin, fibronectin, proteoglycans, and embedded growth factors, is the distinguishing feature for malignancy
Benign proliferative disorders may have organized epithelial-stromal architecture with clear disruption
Diagnosis and treatment of cancer occur generally early in the course of disease.
Cancer = Proliferation + Invasion
Tumors of comparable size and histology can have widely divergent invasive and metastatic potential, depending on their genotype and local environmental influences.
The potential for invasiveness and metastasis are dependent on the genetic, epigenetic and biochemical changes within the tumor cells, but not influenced by all components of the local microenvironment, such as local stroma, inflammation, and local vascular activity
Metastasis is a more eﬃcient process than invasion , where microinvasion may be ongoing without subsequent entry into the vascular portals of dissemination.
The interactions bewteen metastasis and invasion result cytokines and chemokines that drive changes in the local immune response, and stromal-tumor interactions
Millions of cells are shed into the circulation daily from locally invasive cancer, but only a small fraction (≈0.01%) is successful at initiating metastatic colonies.
Tumor-induced neovascularization and invasion are obligate late events
The angiogenic switch has been shown to precede actual malignant transformation in many cancers.
Local microinvasion can occur early, even though distant dissemination may not be evident or may not yet have begun.
Cause of death in cancer patients is 90% Primary tumor and 10% from Metastases
Propensity to metastasize varies greatly between tumors from different tissues
About 30% of patients will have clinically detectable metastases at the time of initial diagnosis, and a further ≈30% of patients will harbor occult metastases
As in many metastasized breast tumors, some structure resembling breast ducts and stroma is reproduced
There is no correlation between tumor size and metastatic potential
Metastatic trait is acquired early in tumor progression => larger tumors have acquired more mutations.
Propensity for metastasis is equal over time but larger tumors dispatch more cells.
Ability to proliferate correlates with ability to metastasize » larger tumors with higher rate of metastasis.
1. Breaching of basement membrane
2. Dissolution of ECM in the subepithelial stroma
(matrix metalloproteinases (MMPs)
cathepsins, other proteases)
3. Migration towards blood vessel
Invasion and metastasis depend on a series of complex biological steps
Angiogenesis is often initiated prior to breach of basement membrane
The Invasion-Metastasis Cascade
1. Primary tumor
2. Local invasion (breakage of BM)
4. Intravascular travel
5. Adherence to endothelium in distant organ(s)
8. Colonization: adjustment to new microenvironment and growth into macrometastasis
Tumor angiogenesis favors extravasation because of incomplete structural vessel integrity.
Breaching of the basement membrane shows less differentiation and the probability of metastases increases, more aggressive
A more differentiated basement expresses more aggressive metastases
TMEM density is a highly predictive marker of metastasis (invasion)
Triad - Tumor Microenvironment of Metastasis (TMEM): Three apposed cellular elements:
1. Carcinoma cell(s): expresses significant levels of Mena actin-cytoskeleton-regulating protein
2. Macrophage: also releases EGF » stimulates carcinoma cell growth
3. Endothelial cell
Immune cells are unable to recognize a variety of tumor-specific and tumor-associated antigens
Subtle differences between normal and neoplastic tissues may allow the immune system to distinguish between these tissues
Tumor-specific transplantation antigens (TSTAs): are only associated with tumor cells, and their expression is not limited to malignant tissues
Tumor-associated transplantation antigens (TATAs): specific to a tumor or a type of tumor and are therefore not present among the repertoire of proteins and oligopeptides normally expressed within the body's tissues.
Tumor-associated transplantation antigens (TATAs): represent the large class of normal proteins that, for one reason or another, have failed to elicit complete tolerance and, when expressed by tumor cells, attract the attention of the immune system.
Tumor-specific transplantation antigens (TSTAs): may be encoded, for example, by viral genomes or by the somatically mutated alleles (such as those of ras, p53, or bcr-abl) arising during tumor progression. Because they are structurally novel, these proteins are unlikely to have induced tolerance during the normal development of the immune system.
Tumor Associated Antigens are normal proteins that are ectopically expressed
Tumors have a limited amount of mechanisms to escape from immune surveillance
MAGE: testicular cell (spermatogonia)-specific antigen; other site: placenta (TATA)
Tyrosinase: expressed in melanocytes, needed for melanin synthesis (TATA)
Reduction in the number on MHC class I molecules can lead to targeting by NK cells
Cancer cells will often down-regulate expression of the MHC class I molecules, ostensibly in order to avoid recognition and attack by cellular components of the adaptive immune response.
Immunoevasive strategies used by cancer cells
Hide Identity, Hide Stress, Inactivate Immunocytes, Avoid Apoptosis, Induce Immunocyte Apoptosis, Neutralize Intracellular Toxins, Neutralize Compliment, Up-regulate CD47 Expression
Anti-tumor Immunity: Lack of T Cell recognition, or inhibition of T cell activation
Immune Evasion by Tumors: T cell recognition of tumor antigen leading to T cell activation
Immune escape from FasL-mediated killing requires two steps for tumor cells
1. Develop resistance to FasL-mediated killing
2. Express FasL themselves and release it » kills lymphocytes expressing Fas Left: Melanoma cells stained with anti-FasL antibody
FasL contributes to immune evasion
FasL: member of death receptor family, ligand of Fas death receptor
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