Invasivity and metastasis Petronini Flashcards
What is the invasiveness and metastasis of cancer cells?
Tumour cells penetrate the basement membrane and invade the surrounding tissues using two modes of movement—individual and collective invasion.
The process by which cancer cells spread to other parts of the body is called metastasis. When observed under a microscope and tested in other ways, metastatic cancer cells have features like that of the primary cancer and not like the cells in the place where the metastatic cancer is found.
THE MECHANISM OF LOCAL INVASION?
Benign tumors grow expansively like cohesive masses, and
thus they remain in the site of origin and have no infiltrative or metastases capacity.
They can disturb nearby tissues by compression. Very often, they have capsules
produced by the stromal component of the tumor. Differently from benign tumors, the
growth of malignant tumors is infiltrative. It is accompanied by
progressive filtration, invasion, and destruction of surrounding tissues
BEHAVIOUR OF NORMAL AND NEOPLASTIC CELLS IN CULTURE?
A) NORMAL CELLS form a monolayer because they
present contact inhibition.
B) CANCER CELLS do not have contact inhibition and
thus they grow overlapping and forming piles (see the
the middle figure (B) on the right).
C) Co-culture of normal and Tumor cells: Cancer cells
without contact, inhibition overlaps normal cells.
What is the reason of the different mode of growth of cancer
cell?
→ Loss of contact inhibition.
→ Growth independently of anchorage.
LOSS OF CONTACT INHIBITION and ANCHOR-INDEPENDENT GROWTH are
linked to?
alterations in cell-cell adhesion molecules (e.g., E-cadherin, N-CAM) and
cell-ECM adhesion related to the presence of integrins.
In invasiveness of malignant cancer cells, there are 4 steps involved:
i. LOSS OF INTRACELLULAR JOINTS
ii. ADHESION - For example, to collagen Type 4, to receptor of fibronectin.
iii. DEGRADATION of extracellular matrix, for example degradation of basal
lamina.
iv. MIGRATION
FACTORS OF INVASIONS?
We move to the most important factors of invasion. For example, in epithelial tumors
(which are called carcinoma) that invade the connective tissue these three factors
play an important role:
1. DETACHMENT FROM PRIMARYCANCER
2. RELEASE OF LYTIC ENZYMES
3. CELLULAR MOTILITY – these cells acquire the capacity to move.
Adhesion molecules:
- E-cadherin is important as an adhesion
molecule in epithelial cells. - Ig superfamily cell adhesion molecules,
for example N-CAM (Neural-Cell Adhesion
Molecule) - Selectins, such as p-selectin which we
studied during inflammation - Integrins
Modification of homotypic adhesion:
In highly invasive carcinomas the
expression of E-cadherins is decreased or absent related to DNA
hypermethylation phenomena. E.g.: Adenocarcinoma of the colon and breast.
Mutations with loss of function are found in stomach and prostate cancer.
In neuroblastoma, N-CAM is present in an immature form that is rich in
sialic acid. Expression is reduced in glioma cells. Increased expression of
N-CAM in many types of neoplasms.
______ is related to epithelial to mesenchymal transition, and thus markers peculiar of
epithelial cells are repressed and markers of mesenchymal phenotype are induced.
EMT,
For example, E-cadherin is not expressed while N-cadherin is expressed, and this
favor the migration of the cell.
Modification in heterotypical adhesion:
In cancer cells, the expression
of integrins is modified mainly in quantitative terms. High expression of
αvβ3 mediates the transduction of mitogenic and antiapoptotic signals,
interacts with extracellular matrix components such as vitronectin, with
metalloproteinase, and stimulates angiogenesis. Hypoexpression of
α3β1, which binds fibronectin, modifies the anchorage of the cancer cell
to the extracellular matrix favoring the invasion process. We can
summarize that there are alterations in adhesion molecules in malignant
Cells. Modification in terms of quantitative or qualitative expression related
to homotypical or heterotypical adhesion
What are the roles of N-cadherin?
→ Promotion of cellular motility
→ Anti-apoptotic activity
Through PI3 Kinase, inhibition of pro-apoptotic molecule, such as Bak and
Bax
What is EMT?
Epithelial to Mesenchymal Transition
Another important aspect is related to epithelial to
mesenchymal transition: The epithelial-mesenchymal
transition is a variation of the phenotype of the neoplastic cell
of epithelial origin that modifies its phenotype in
mesenchymal sense, acquiring invasive capacity. The loss of
E-cadherin expression and the increase of vimentin and N-cadherin are crucial events in EMT and are caused by
modifications of gene expression by the transcriptional factors
SNAIL and TWIST. You can see in the picture on the right a
tumor which has a loss of expression of E-cadherin in many
cells.
We can conclude that there is a _________________ due to the increased
expression of N-cadherin that affect the polarization of Rho and GTPase
signaling
neurogenic affect
Tumors release:
☼ Serineprotease – such as plasmin.
☼ Cysteineinprotease – such as catepsin D.
☼ Matrix metalloproteases (MMP) – collagenase type VI, gelatinase, elastase.
☼ Activator of plasminogen – Urokinase, type plasminogen activator (U-PA),
which produces plasmin
The tumor not only produces proteases but also produces inhibitors of
metalloproteases – TIMP (Tissue Inhibitors of Metalloproteases). Related to this
aspect, assuming a tumor that is very invasive, what is the ratio between proteases
compared to TIMP? A higher expression of enzymes and a lower expression of
TIMP. We will talk about metastosuppressor genes and genes that increase the
ability of a tumor to metastase. In this case, the gene that codifies for TIMP is a
metastosuppressor gene. Meanwhile, the gene that codifies for collagenase type IV is
a metastogene
Degradation of the ECM releases ________ and _______ factors immobilized in the
matrix.
growth, motility
__________ is a multifasic process involving numerous surface receptors that
activate signal transduction pathways and cytoskeleton modifications
Cell migration
When you have a patient with malignant tumor, you
have to perform some examinations to show the presence of metastases, like _____________________
PET
(positron emission tomography).
What is the tumor that frequently metastases in the liver through blood?
Colon tumor, due to the portal vein anatomy
About ___ of patients
have metastases at the time of diagnosis of malignant tumor
30%
Stages of metastatic process:
- Separation from primary cancer
- Crossing of the stroma
- Dissemination – through lymphatic or blood vessels
- Arrest in a new location.
Pathways of dissemination of metastasis:
→ Blood: It is preferred by Sarcomas, initial Carcinomas (e.g., renal, thyroid,
hepatic)
8
→ Lymphatic: It is preferred by Carcinomas.
→ Diffusion in cavities or transcelomatic – For example, Carcinomas of the
stomach, ovary, and colon that metastasize into the peritoneal cavity. Breast, lung, and esophageal carcinomas may metastasize into pleural and/or pericardial
cavities.
→ Contiguity: To the cheek from a tumor of the gum mucosa, in the liver from a
carcinoma to the head of the pancreas. The first symptom when you have a
patient with adenocarcinoma of the pancreas is related to some problem
with the liver, the yellow color of the skin, due to the compression of this tumor
to some part of the liver.
→ By grafting or iatrogenic: during the enucleation of the tumor by the
surgeon.
Arterial diffusion is
typical of _____________
Lung cancers, Thus, lung cancer can metastases in all parts of the body,
with some preferential sites such as in the brain
Stages of blood route diffusion:
▪ We start with metastatic clones, clonal expansion, growth, appearance of
different clones.
▪ Exceeding the basal membrane.
▪ Penetration into the vessel.
▪ Embolism of cancer cells, platelets, and fibrin.
▪ Adhesion to the membrane, leaking from the vessel.
▪ Tumor growth and angiogenesis (growth of blood vessels).
Neoplastic embolisms?
They are formed by cancer cells that aggregate with platelets and activate clotting
factors. Which enzyme is important during clotting? Thrombin, that convert fibrinogen
9
to fibrin. The expression of CD44 by cancer cells seems to favor its leakage from the
vessels, due to its ability to bind the hyaluronic acid present on the endothelium at
the capillary level.
