Lecture 7: Multi-Step tumorigenesis & Metastasis Flashcards
Primary Site
Term to describe the original, first tumor in the body
Staging
Refers to the grouping of patients according to the extent of their disease
Metastatic Cancer
When primary cancer disseminates to other organs and forms a new, secondary tumor that will be the same type as the primary tumor
As of 2019, cancer is the ______ leading cause of death in the United States behind ____________, and the majority of patients who die of cancer, die of __________.
Second
Cardiovascular disease
Metastases
Transplacental transmission of malignant cells is rare. Metastatic disease appeared at birth to ______ months of age at least _________% of patients have died from metastatic tumors.
20
65%
Cancer Stage
Staging is a description of the gross appearance of the tumor including size, invasion, spread to local sites & lymph nodes, or metastasis.
Cancer Grade
Grading is a description of the microscopic appearance of the tumor’s cells and tissue.
TNM Abbreviation
T: Size & extent of the main primary tumor
N: Number of nearby lymph nodes containing cancer cells
M: Whether the cancer has metastasized.
(Tumor, Node, Metastasis)
TNM System
System for classifying a malignancy to provide information about the anatomic extent of invasion and tumor size.
T1 in TNM System
Less than 2 centimeters
T2
2-5 Centimeters
T3
Greater than 5 centimeters
T4
Tumor over 5 centimeters
TX
Tumor can not be measured
T0
Tumor cannot be found
NX
Cancer in the nearby lymph nodes cannot be measured
N0
There is no cancer in the nearby lymph nodes
N1,N2, N3
Number and location of lymph nodes that contain cancer. The higher then N, the more lymph nodes contain cancer.
MX
Metastasis cannot be measured
M0
Cancer has not spread to other parts of the body (No metastasis)
In situ
Abnormal cells present but have not spread to nearby tissue
M1
Cancer has spread to other parts of the body (Metastatic)
Localized
Cancer is limited to the place where it started, with no sign it has spread
Regional
Cancer has spread to nearby lymph nodes, tissues, or organs
Distant
Cancer has spread to distant parts of the body
Unknown
Not enough information to figure out the stage
Skin metastasis from internal organs has a _________ to ______% incidence and ________ metastasis is much rarer.
5-10%
Zosteriform
Probable mechanism for band-distributed skin metastasis
The retrograde flow of lymph after obstruction by cancer cells
Mechanism of inflammatory breast cancer
Cancer cells block the smallest lymph package of the breast
Breast-Conserving surgery
Removes cancer while leaving as much normal breast as possible
Tumor Grade
Description of tumor based on histology: How abnormal the tumor cells and the tumor tissue looks under a microscope
“Well differentiated”
When the cells of the tumor and the organization of the tumors tissue are close to those of normal cells and tissue. These tumors grow and spread at slower rates
“Undifferentiated” or “Poorly Differentiated”
Tumors have abnormal looking cells and may lack normal tissue structures. These tumors grow faster and are closer to becoming metastatic
Grade 1
Well Differentiated (Low Grade): Cancer cells that resemble normal cells and aren’t growing rapidly
Grade 2
Moderately differentiated (Intermediate grade): Cancer cells that don’t look like normal cells and are growing faster than normal cells
Grade 3
Poorly Differentiated (High grade): Cancer cells that look abnormal and may grow or spread more aggressively
Grade 4
Undifferentiated (High grade): Tumor cells look most abnormal
TP53
Tumor marker capable of improving prognosis accuracy. In endometrial endometrioid carinoma, reclassified G1/2 from low grade to high grade
MSK-IMPACT
Identified actionable genetic changes in 37% of patients with advanced solid cancers
Actionable Mutation
One that can be targeted with either an approved drug or one being tested in clinical trials
Non-cancer deaths among patients who live with metastatic cancer may largely be divided into 2 groups
- Chronic comorbid conditions
2/ Acute, iatrogenic, or treatment-induced infections
Mutation requirements for cancer
- 1-10 mutations needed
- Half of the coding driver mutations occur outside of known cancer genes
- Genomic instability is a cornerstone of cancer
Driver Mutations
Mutations that provide growth advantage and promote cancer development
Passenger mutations
Those that do not provide growth advantage or promote cancer development
Most mutations in driver genes that were shared between primary and metastatic tumors were predicted to have __________
Functional consequences
Within individual patients, a large majority of driver gene mutations are common to _____ metastases
All
6 Cascading process of metastasis
- Epithelial to mesenchymal transition (EMT)
- Invasion to surrounding tissue
- Intravasation to blood vessels
- Survival in circulation
- Extravasation to colonize and thrive at distant sites
- Organotropism/Organ-specific metastasis
Studies such as Lee-Fraumeni patients and mutant p53 knock-in mice provide a strong case for p53 mutations acting as the ___________ for tumorigenesis
Initial driving force
Tumor suppressors are driver genes in which driver mutations are ______
Inactivating
Liver metastasis occurs in ________% of adults dying of cancer
40-50%
Oncogenes are definted as driver genes in which driver mutations are ___________ or result in new functions
Activating
____________ rather than the age at which exposure began determines likelihood of developing a detectable tumor
Cumulative exposure
The ________________ has _________ which allow malignant to escapes circulation and enter liver parenchyma
- Sinusoidal epithelium
- Fenestrations
Multistep tumorigenesis
Histopathological progression from normal cells to cancer cells
1. Hyperplasia
2. Adenoma/Dysplasia
3. Carcinoma
4. Metastasis
LOH in colon tumor progression
Early adenoma often has LOH in the long arm of chromosome 5
CIS
Carcinoma in situ
Almost half of slightly larger adenomas carried, in addition, a ______ _______ oncogene
mutant k-ras
DCIS
Ductal carcinoma in situ
CIN
Cervical intraepithelial neoplasia
Around half of all carcinomas showed an ______ on the short arm of chromosome ______
LOH
17
Larger adenomas tend to have high rates of LOH on the long arm of chromosome ________
LOH
18/18q
PIN
Prostatic intraepithelial neoplasia
Genomes of most evolving, pre-neoplastic growths were found to suffer widespread _____
HYPOmethylation
Consequences of hypomethylation
Chromosomal instability
Aberrant crypt foci often carry an ___________________ together with an activated _______ oncogene
- Inactivated APC tumor supressor gene
- K-ras
At the primary tumor site, a tiny fraction of long term self renewing ___________ may represent early MICs with driver mutations and high cellular plasticity
Tumor-initiating cells (TICs)
Epithelial-mesenchymal plasticity of metastatic cells
Acquisition of stem cell-like properties
Metabolic reprogramming of metastatic cells
MICs may require a high metabolic adaptability and metabolic stress resistance. Different host organs also have different nutrients and oxygen conditions
Hypoxia inducible factor-1 (HIF-1)
Factor activated by metastatic breast cancer cells in bone go survive hypoxia and increased angiogenesis
Resistance to apoptosis & upregulation of anti-apoptotic pathway of metastatic cells
High expression of anti-apoptotic proteins such as Bcl-xL and Bcl-2
Organotropism
Non-random distribution among distant organs
Factors regulating organotropism
-Circulation pattern
-Tumor-intrinsic factors
-Organ specific niches
-Interactions between tumor cells and host micro environment
