MBB 446 Lecture 3 Flashcards
What is the most common type of staging system used
TNM staging system
Benefit of TNM staging system
Provides a “common language” for doctors
What 3 components is TMN based on
- T (Tumor) - indicate size of PRIMARY tumor and degree of spread into nearby tissues (local invasion)
- N (lymph nodes) - indicates whether or not cancer has spread to nearby lymph nodes, the size of nodes that contain cancer and how many lymph nodes contain cancer
- M (Metastasis) - indicates whether or not cancer has spread (metastasized) to distant organs
Additional letters or numbers are placed after T, N and M to provide more specific details. What is the meaning of the following letters/#’s
- X
- T followed by a #
- N followed by a #
- M followed by a #
- Lowercase letters
- X means the tumour or lymph nodes cannot be assessed or evaluated.
- T followed by a # (0–4) describes the size of tumour and how much nearby tissue it has invaded.
- N followed by a # (0–3) describes the degree of spread to the lymph nodes.
- M followed by the # 0 or 1 describes whether or not cancer has spread to other parts of the body.
- Lowercase letters (a, b or c) are used to subdivide the tumour, lymph nodes or metastasis categories to make them more specific.
Describe a T1N1M0 tumour
small tumor with low level of regional lymph node involvement but no distant metastases
Describe a T3N2M1 tumour
large tumor with regional lymph node involvement and also distant metastases (secondary tumors) detected
What are the main steps/phenotypes of tumor progression?
- Normal
- Hyperplastic
- Dysplastic
- Neoplastic
- Metastatic
Describe hyperplastic growths
- contain excessive #’s of cells;
- cells retained ability to assemble into tissues that appear reasonably normal
Describe metaplasia
- one type of normal cell layer is replaced by cells of another type that are not normally present in this site within a tissue (eg. via differentiation; from normal to abnormal)
- the “invaders” appear completely normal
- frequent in epithelial transition zones where one type of epithelium meets another
Describe Barret’s esophagus
-SQUAMOUS cells that normally line the esophagus wall are replaced by SECRETORY cells from the lining of the stomach; can become a precursor lesion to an esophageal carcinoma
Describe dysplasia
- cells are usually abnormal cytologically (e.g. change in nucleus size, shape etc.)
- Relative #’s of the various cell types seen in the normal tissue no longer observed
- Changes have major effects on overall tissue architecture
Example of cytological changes, as seen in dyplastic tissues
- variability in nuclear size and shape
- increased nuclear staining by dyes
- increased ratio of nuclear vs cytoplasmic size
- increased mitotic activity
- lack of normal cytoplasmic features
Which phase/step in tumorigenesis is considered to be a transition state between completely benign growths and premalignant growths?
Dysplasia
Examples of large, readily detectible growths?
adenomas, polyps, adenomatous polyps, papillomas, (and warts)
How do large, readily detectible growths e.g. adenomes, differ from normal epithelial tissue? Is growth continuous, and if so until when?
- Contain all the cell types found in the normal epithelial tissue but have increased growth
- Usually grow to a certain size and then stop
- Do not penetrate the basement membrane and do not invade underlying tissues (ie. benign)
What tissue stage/phenotype would growths like adenomes be classified as?
Dysplastic
Examples of dysplastic tissue
Adenomas, polyps, adenomatous polyps, papillomas, and warts
Describe neoplasia
- New types of tissue
- Includes growth that INVADE underlying tissue
- Tumors are now considered malignant and have substantial life-threatening potential
What is the process metastasis?
Primary tumor seeds new tumor colonies by the process of INVASION of adjacent tissues, entry into BLOOD and LYMPH vessels, exit from vessels and INVASION of underlying tissue, formation of a new tumor at distant site
Metastases in _____ often arise in patients with advanced colon carcinomas.
Liver
Why do metastases in liver often arise in patients with advanced colon carcinomas.?
The portal vein drains blood from the colon to the liver – providing a route for metastasizing colon cancer cells.
Breast cancer often metastasizes to the ____
Brain
___% of patients with breast cancer will develop brain metastases
20-30%
Summarize the steps in tumor progression
1) Normal
2) Hyperplasia
3) Dysplasia
4) Neoplasia
5) Metastatic
- Normal
- Hyperplasia:
- increased # of cells
- usually doesn’t progress
- benign - Dysplasia
- Cytological changes
- 3 grades of dysplasia
- “high” grade dysplasia usually progresses and thus is treated
- still non-invasive - Neoplasia = cancer
- increased morphological changes
- can be “in situ” aka locally invasive or “malignant” (but still in primary origin), or show “distant invasion” (i.e. another organ) - Metastasis
- enters blood stream or lymph
- tumor recurs in second (or more) site
Note: Metaplasia typically involves cell type conversion (so does not necessarily involve disruption of basement membrane) and can occur at ANY of the steps
What is polypectomy
surgical removal of polyps
in patients who have undergone polypectomy (red line), the observed numbers of colorectal cancers diagnosed in subsequent years is _____ by > 80%
reduced
Metastases: responsible for approximately ___% of cancer related deaths
90%
FDG uptakes indicates regions of high glucose uptake associated with _____
aerobic glycolysis
Metastatic carcinoma cells (blue) in the bone marrow can be revealed by _____ to detect cells displaying epithelial markers;; sets them apart from cells naturally present in the marrow
Immunohistochemistry (IHC)
As the size of primary tumor inc, the risk of metastasis _____
inc
What are the 8 steps in the invasion-metastasis cascade?
- Primary tumor formation
- Localized invasion
- Intravasation
- interaction w/platelets, lymphocytes, and other blood components - Transport thru circulation
- Arrest in microvessels of various organs
- Extravasation
- formation of micrometastasis
- colonization of a macrometastasis
Define intravasation
process of invading a blood or lymphatic vessel from the surrounding tissue
Define extravasation
process of leaving a blood or lymphatic vessel and invading the surrounding tissue
Define micrometastasis
a metastasis that is composed of a single cell or a small clump of cells and is only apparent through microscopy (< 2mm diameter)
Define macrometastasis
large clump of cells;; detectable by palpation, imaging (clinically detectable)
____ Cells play vital roles during the Invasion-Metastasis Cascade
Stromal
Describe the steps in the invasion-metastasis cascade and the role of the different chemical components
- Primary tumour formation
- Local invasion
- Proteases like capthesin degrade BM and ECM, also liberate tethered GFs - Intravasation
- CSF-1, EGF (released by macrophages) - Survival in circulation
- Circulating tumour cell (CTC) express ligands to selectins (vascular cell adhesion molecules expressed on platelets and Endothial cells), help to survive shear forces and evade immune destruction - Arrest at a distant organ
- Extravasaion
- Angiopoietin-like-5 (signalling protein) acts to disrupts vascular endothelial cell-cell jxns - Microtumour formation
- Matrix metallo-protease (MMP)
- SDF-1 (stromal cell-derived factor-1; carcinoma cell chemoattractant) for “priming” - Colonization of macrotumour
- OPN (osteopontin; a secreted phosphoprotein that promotes priming) - Clinically detectable macroscopic metastases
What is the role of CSF-1 and EGF in invasion and intravasatio
EGF (Epidermal Growth Factor):
- tethered to cells in the STROMA
- released by MMPs (marix metalloproteinases)
- acts to support tumor cell proliferation and survival
EGF and CSF-1 (Colony Stimulating Factor-1) both enhance invasion and intravasation:
- tumor associated macrophages (TAMs) and carcinoma cells both secrete these growth factors (reciprocal stimulation)
“communication loop involving secretion of CSF-1 by cancer cells that would activate macrophages to secrete EGF, a chemoattractant for the cancer cells that would drive their invasion”
Describe how EMT enables invasion
- Carcinoma in situ
- Progression
- EMT invasion - Intravasation of EMT
- Transport thru circulation
- Extravasation
- EMT to MET - Micrometastasis
- Colonization of macrometastasis
What are the cellular and molecular changes associated with EMT
Loss of
- Cytokeratin expression
- E-cadherin
- Epithelial cell polarity and epithelial gene expression program
Acquisition of
- Fibroblast like shape
- Motility
- Invasiveness
- N-cadherin
What are CTCs
- Circulating tumour cells = tumor cells within the bloodstream of carcinoma patients i.e. represent carcinoma cells that are en route between primary tumors and sites of dissemination
- Metastatic intermediates
What stresses must CTCs survive?
- resistant to anoikis, hemodynamic shear forces, immune escape
- likely exist in circulation for only minutes before being trapped in various capillary beds
Explain the Kaplan Meier survival plot seen on Lecture 3 Slide 43 (a)
Kaplan Meier plots survival on the y axis, here specifically probability of survival free of macrometastases. The x axis plots time, here, the number of months after surgery. Blue line represents population who had no micrometastases, and red line represents population with micrometastases. Data shows that if micrometastases are present, there is a reduced probability of survival free of macrometastases.
Explain the Kaplan Meier survival plot seen on Lecture 3 Slide 43 (b)
Kaplan Meier plots survival on the y axis, here specifically cumulative survival. The x axis plots time, here, the number of years since entry into clinical trial or treatment. Data shows that patients with no micrometastases had a higher cumulative survival rate than those with micrometastases.
What are Kaplan Meier survival plots?
a convention for graphing various clinical observations in which the % of surviving patients (or other clinical parameter such as disease-free or progression-free survival is plotted on the Y axis while the time course after initial diagnosis or treatment is plotted on the X axis
In kaplan meier plots, how is survival probability plotted?
For each time interval, survival probability is counted as the number of patients surviving divided by the number of patients at risk
- Kaplan Meier plots allows estimation of survival over time, even when patients ________ or ________
- (if drop out, patient is said to be “______” and not included in the total number, ie. denominator)
- drop out or are studied over different lengths of time
2. censored
Carcinomas originating from a particular epithelial tissue form detectable metastases in only a limited subset of theoretically possible distant organ sites. What factors influence where metastases can form?
- Circulation
2. ability of tumor cells to adapt to microenvironment
For primary tumours in the breast, where are the 4 common distant metastases sites?
- Brain
- Bone
- Lung
- Liver
For primary tumours in the colon, where is the 1 common distant metastases sites?
- Liver
For primary tumours in the stomach, where are the 3 common distant metastases sites?
- Brain
- Lung
- Liver
For primary tumours in the lung, where are the 3 common distant metastases sites?
- Brain
- Liver
- Adrenal gland
For primary tumours in the prostate, where is the 1 common distant metastases sites?
- Bone
Why is the brain considered a sanctuary for metastatic tumor growth?
The BBB and other components of the brain microenvironment, provide PROTECTION to the tumor cells from IMMUNE SURVEILLANCE, CHEMOTHERAPEUTICS and other potentially harmful substances.”
What is the seed and soil hypothesis?
The ability of a disseminated CANCER CELL (the seed) to successfully found a metastasis depends on whether a distant tissue offers it a HOSPITABLE environment (the soil) to survive and proliferate.
Describe the inefficient steps of the invasion-metastasis cascade
- Pool of potential metastatic cells
- Extravasation (20% attrition)
- 20% cumulative attrition) - Microformation (96% attrition)
- 97% cumulative attrition - Metastatic colonization (99.3% attrition)
- 99.98% cumulative attrition
Which step in particular the invasion-metastasis cascade is the rate limiting step
the process of metastatic colonization
What % of the remaining cells is tumor-initiating cells
0.02%
Describe the traditional vs. evolving view of metastasis in regards to priming the distant sites
Traditional view: Primary tumor cells escape site or origin, travel in unidirectional path away from primary site and ultimately colonize distant organs to give rise to systemic disease
Evolving view: Inflammatory factors from the tumor act to mobilize bone-marrow-derived cells that serve to prime distant sites of metastasis.
