Lecture 7: Multi-Step tumorigenesis & Metastasis Flashcards by Manuel Custodio

Primary Site

Term to describe the original, first tumor in the body

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Staging

Refers to the grouping of patients according to the extent of their disease

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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

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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

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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.

65%

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Cancer Stage

Staging is a description of the gross appearance of the tumor including size, invasion, spread to local sites & lymph nodes, or metastasis.

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Cancer Grade

Grading is a description of the microscopic appearance of the tumor’s cells and tissue.

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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)

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TNM System

System for classifying a malignancy to provide information about the anatomic extent of invasion and tumor size.

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T1 in TNM System

Less than 2 centimeters

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2-5 Centimeters

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Greater than 5 centimeters

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Tumor over 5 centimeters

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Tumor can not be measured

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Tumor cannot be found

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Cancer in the nearby lymph nodes cannot be measured

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There is no cancer in the nearby lymph nodes

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N1,N2, N3

Number and location of lymph nodes that contain cancer. The higher then N, the more lymph nodes contain cancer.

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Metastasis cannot be measured

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Cancer has not spread to other parts of the body (No metastasis)

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In situ

Abnormal cells present but have not spread to nearby tissue

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Cancer has spread to other parts of the body (Metastatic)

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Localized

Cancer is limited to the place where it started, with no sign it has spread

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Regional

Cancer has spread to nearby lymph nodes, tissues, or organs

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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

1. Chronic comorbid conditions 2/ Acute, iatrogenic, or treatment-induced infections

Mutation requirements for cancer

1. 1-10 mutations needed 2. Half of the coding driver mutations occur outside of known cancer genes 3. 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

1. Epithelial to mesenchymal transition (EMT) 2. Invasion to surrounding tissue 3. Intravasation to blood vessels 4. Survival in circulation 5. Extravasation to colonize and thrive at distant sites 6. 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

1. Sinusoidal epithelium 2. 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

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

1. Inactivated APC tumor supressor gene 2. 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