Hallmarks of Cancer - Full Explanation

1. Growth Signal Self-Sufficiency

2. Anti-Growth Signal Insensitivity

• Tumor suppressor gene mutations (eg, Rb): The retinoblastoma protein (Rb) normally acts as a brake on the cell cycle. When Rb is phosphorylated and inactivated by cyclins/CDKs, the cell proceeds through G1. In cancer, Rb is lost/mutated, so the brakes are permanently off. Requires loss of BOTH alleles (recessive - "two-hit hypothesis").
• Loss of E-cadherin / contact inhibition: E-cadherin is an adhesion molecule that tells a cell "I'm surrounded by neighbors, stop dividing." When lost, cells lose contact inhibition and pile up. The NF2 protein (merlin) acts downstream of E-cadherin to mediate this signal - NF2 mutations cause neural tumors (neurofibromatosis type 2). - Robbins Basic Pathology, p. 237

3. Evasion of Apoptosis

• TP53 mutations: p53 is the "guardian of the genome." DNA damage normally activates p53 → cell cycle arrest (via p21) → DNA repair or apoptosis (via PUMA, BAX). When TP53 is mutated (found in >50% of all human cancers including lung, colon, breast), cells with damaged DNA survive and keep dividing. - Robbins Basic Pathology, p. 236-237
• BCL2 overexpression: BCL2 is an anti-apoptotic protein. In follicular B cell lymphoma, the t(14;18) translocation fuses BCL2 to the immunoglobulin heavy chain gene, causing massive BCL2 overexpression. Lymphocytes accumulate because they can't die - the tumor grows slowly but relentlessly. - Robbins Basic Pathology, p. 145

4. Limitless Replicative Potential

1. Normal cells → telomeres shorten with each division → replicative senescence → cell death
2. Cancer cells → reactivate telomerase (an enzyme that adds telomere sequences back) → telomeres are maintained → cells become immortal

5. Sustained Angiogenesis

• Increased VEGF (Vascular Endothelial Growth Factor) - produced by tumor or stromal cells
• Decreased inhibitors (eg, thrombospondin-1)
• Vessels sprout from existing capillaries (neoangiogenesis) or new endothelial cells are recruited from bone marrow (vasculogenesis)
• Tumor vessels are typically leaky and dilated (irregular architecture), which also facilitates tumor cell escape into the bloodstream

6. Warburg Effect (Altered Cellular Metabolism)

7. Immune Evasion

8. Tissue Invasion

Loss of E-cadherin 
   → Loosening of intercellular junctions 
      → Metalloproteinases (MMPs) degrade basement membrane and ECM 
         → Tumor cells attach to ECM proteins (laminin, fibronectin) 
            → Cells migrate through degraded ECM ("locomotion") 
               → Enter blood/lymphatic vessels (vascular dissemination)

9. Metastasis

1. Local invasion (as above) → enter lymphatics or blood vessels
2. Survival in circulation (most cells die here)
3. Adhesion to endothelium at the target organ
4. Extravasation (exit vessels) and homing to new tissue
5. Colonization - grow in the new microenvironment

• The target organ is often the first capillary bed encountered after leaving the primary tumor (eg, colon cancer → portal circulation → liver)
• Some cancers show organ tropism regardless of anatomy (eg, lung cancer metastasizes to adrenals; breast cancer to bone, brain, lung, liver)

Summary Mnemonic: "GEALW-IIM"

Page 218 - Immune Checkpoint Interactions & Cancer Epidemiology

Part 1: Immune Checkpoint Interactions

Background - What is a Checkpoint?

1. Signal 1: T cell receptor (TCR) recognizes antigen presented on MHC (on APC or tumor cell)
2. Signal 2 (costimulation): CD28 on the T cell binds B7 on the APC → activating "+", proliferative signal

Checkpoint 1: CTLA-4 Pathway

APC has B7 on its surface
  ├─ CD28 on T cell binds B7 → (+) ACTIVATION signal → T cell proliferates
  └─ CTLA-4 (expressed LATER on activated T cells) also binds B7
       but with HIGHER affinity than CD28
         → OUTCOMPETES CD28 for B7
         → Removes the costimulatory (+) signal
         → T cell activation is turned OFF

• A monoclonal antibody that blocks CTLA-4
• CTLA-4 can no longer compete with CD28
• CD28 binds B7 freely → costimulatory signal restored → T cells attack tumor
• First approved in 2011 for advanced melanoma
• Side effects: autoimmunity - colitis, hepatitis, dermatitis (because you've removed a normal brake) - Cellular & Molecular Immunology, p. 971-973

Checkpoint 2: PD-1 / PD-L1 Pathway

Tumor cell expresses PD-L1 on its surface
  → PD-L1 binds PD-1 on activated T cells
  → Activates ITIM motif → phosphatases dampen TCR signaling
  → T cell becomes "exhausted" (dysfunctional)
  → Tumor cell escapes killing

• CTLA-4 acts early - in lymph nodes, at the costimulation stage
• PD-1/PD-L1 acts late - at the tumor site itself, on already-activated T cells
• This is why PD-1 blockade is often more targeted/less autoimmune side effects than CTLA-4 blockade

Why Two Different Checkpoint Targets?

Part 2: Cancer Epidemiology

Important note: Skin cancer (basal cell > squamous cell >> melanoma) is the MOST COMMON cancer overall, but it is excluded from most ranking tables because it is almost never fatal and not tracked the same way.

Cancer Incidence (who GETS it)

Cancer Mortality (who DIES from it)

High-Yield USMLE Memory Points

Putting It Together: The Big Picture

Common Metastases - Full Explanation

The Key Rule: CLaSH

Carcinomas spread via Lymphatics; Sarcomas spread Hematogenously = CLaSH

The 4 Exceptions - "CLaSH Breakers"

1. Follicular thyroid carcinoma - invades through the thyroid capsule into blood vessels; confirmed by vascular invasion on histology. - Cummings Otolaryngology, p. 3963
2. Choriocarcinoma - highly vascular trophoblastic tumor; enters blood rapidly
3. Renal cell carcinoma (RCC) - notorious for growing directly into the renal vein and inferior vena cava as a tumor thrombus
4. Hepatocellular carcinoma (HCC) - develops in a vascular organ with sinusoidal blood flow

General Rules About Metastases

• Metastasis to bone, liver, lung, and brain is MORE COMMON than primary malignancy in those organs
• Metastases typically appear as multiple lesions (vs. primary tumors which appear as a solitary lesion)
• This distinction is critical on imaging - multiple lesions in the liver or brain = think metastases first

The 4 Major Sites of Metastasis

1. Bone Metastasis

• Pain (most common symptom)
• Pathologic fractures (bone weakened by lysis)
• Hypercalcemia (from lytic destruction releasing calcium)
• Spinal cord compression (from vertebral metastases - axial skeleton predilection)
• Anemia (marrow replaced → less red cell production)

2. Liver Metastasis

• Elevated ALP, GGT (cholestatic pattern)
• Hepatomegaly, right upper quadrant pain
• "Cannon ball" nodules on imaging in aggressive cases (eg, RCC, choriocarcinoma)

3. Lung Metastasis

4. Brain Metastasis

• Blood vessels narrow abruptly at the interface between cortex (gray matter) and white matter
• Tumor emboli slow down and lodge here, like debris caught at a bottleneck
• This is why brain mets appear as multiple discrete nodules right at this junction

Summary Table - All Metastatic Sites

High-Yield USMLE Integration