Molecular Basis and Mechanisms of Neoplasia

What is the definition of neoplasia?

New growth

What is a tumor?

A collection of cells and stroma

What is oncology?

The study of tumors

How are benign tumors named?

Tissue name + "-oma"

What is a chondroma?

A benign cartilaginous tumor

What is an adenoma?

A benign tumor of glandular structures

What is a polyp?

A benign grossly visible projection above a mucosal surface

What is a sarcoma?

A malignant tumor of mesenchymal tissues

What is a carcinoma?

A malignant tumor of epithelial cells

What is a melanoma?

A malignant tumor of melanocytes

What is the estimated percentage of lung and bronchus cancer incidence in men?

13%

What is the estimated percentage of lung and bronchus cancer incidence in women?

13%

What is the estimated percentage of prostate cancer incidence in men?

20%

What is the estimated percentage of breast cancer incidence in women?

30%

What is the estimated percentage of colon and rectum cancer incidence in men?

9%

What is the estimated percentage of colon and rectum cancer incidence in women?

7%

What is the estimated percentage of lung and bronchus cancer deaths in men?

24%

What is the estimated percentage of lung and bronchus cancer deaths in women?

23%

What is the estimated percentage of prostate cancer deaths in men?

10%

What is the estimated percentage of breast cancer deaths in women?

15%

What is the estimated percentage of colon and rectum cancer deaths in men?

9%

What is the estimated percentage of colon and rectum cancer deaths in women?

8%

How many cancer-related deaths occur worldwide annually?

9.5 million deaths worldwide

Which four types of cancer constitute more than 50% of diagnoses?

Lung, female breast, prostate, and colon/rectum cancer

What age group has the highest incidence of cancer?

Most cases occur in individuals older than 55 years of age.

What is the leading cause of death among women aged 40 to 79?

Cancer

What is the leading cause of death among men aged 60 to 79?

Cancer

What percentage of all deaths in individuals younger than 15 years old are due to cancer?

10%

What are the three most common cancers in children younger than 15 years old?

Acute leukemia, neuroblastoma, and retinoblastoma

What is a precursor lesion?

A localized morphologic change that identifies a field of epithelium at increased risk of malignant transformation.

How does chronic inflammation relate to cancer risk?

It increases cancer risk in individuals affected by various chronic inflammatory diseases, both infectious and noninfectious.

What is an inherited genetic change related to cancer?

A genetic change that increases cancer risk and can be passed down if present in a parent's egg or sperm cells.

How does chronic inflammation related to cancer risk?

It increases cancer risk in individuals affected by various chronic inflammatory disease, both infectious and noninfectious.

What is an inherited genetic change related to cancer?

change that increase cancer risk and can be passed down if present in a parent’s egg or sperm cells.

APC gene is associated with

colorectal cancer (FAP)

gene BRCA1/BRCA2 is associated with what condition

BRest, prostate CAncer

DCC tumor suppressor gene not active in

associated condition - colorectal cancer

gene SMAD4 (DPC4) is associated with what condition

pancreatic cancer, colorectal cancer

Gene PTEN is associated with what condition

prostate, breasT

gene RB1

associated condition: Retinoblastoma.

gene TP53 is associated with what condition

multiple malignancies Breast/Brain, Lung/Leukemia, Adrenal gland.

RB1

Associated with Retinoblastoma

TP53

Known as the "Guardian of the Genome"

TP53 Function

Regulates cell cycle progression, DNA repair, cellular senescence, and apoptosis

TP53 Mutation

Most frequently mutated gene in human cancers 🚨

What factors can cause DNA damage leading to p53 activation?

ionizing radiation, carcinogens, and mutagens.

what happens when p53 detects DNA damage?

it accumulates, binds to DNA, and activates transcription-dependent and independent targets

What are the possible cellular responses when p53 is activated?

-Senescence (permanent cell cycle arrest)

-G1 arrest and DNA repair (via p21 and GADD45)

-Apoptosis (BAX and PUMA if repair fails)

what happens if p53 is mutated or lost?

p53 dependent genes are not activated

-no cell cycle arrest, no DNA repair, no senescence

-mutant cells accumulate mutations

-leads to malignant tumor formation

What are two key proteins involved in p53-mediated apoptosis?

BAX and PUMA (pro-apoptotic proteins)

Environmental Factors & Lung Cancer

90% of lung cancers are caused by environmental factors

alcohol Smoking & Cancer Risk

Affects mouth, esophagus, pancreas, and bladder

Pharynx & Larynx Cancer Risk increased by

alcohol Increases risk of pharynx carcinoma, larynx, and esophagus cancer

Estrogen & Cancer Risk

Lifelong estrogen exposure increases risk of breast & endometrial cancers

Cancer Risk Increase by Gender unhealthy food intake environmental factors

52% in males 🔹 62% in females

toxin: Arsenic

Organ: lung

toxin: asbestos

Organ: lungs

toxin: Tobacco smoke

Organ: lung

toxin: ethanol

organ: breast

toxin: nickel, chromium beryllium, silica

organ: lungs

toxin: Radon

organ: lungs

what are the cellular and molecular hallmarks of cancer?

-sustaining proliferative signaling.

-enabling replicative immortality

-Tumor-promoting inflammation

__

-evading growth suppressors

-genome instability

__

-avoiding immune destruction

-resting cell death

__

-activating invasion & metastasis

__

-inducing or accessing vasculature

-deregulating cellular metabolism

Warburg Effect

Cancer cells exhibit altered metabolism

Glucose & Cancer Metabolism

Cancer cells use high levels of glucose for energy

Fermentation in Cancer Cells

Glucose → Lactate even in the presence of oxygen (aerobic glycolysis)

How does glucose metabolism differ in differentiated vs. proliferaating tissue?

Differentiated tissue: uses oxidative phosphorylation when oxygen is available. and anaerobic glycolysis when oxygen is absent.

Proliferating Tissue (including cancer cells): uses aerobic glycolysis (Warburg effect), favoring lactate production regardless of oxygen availability.

What enzyme is involved in converting pyruvate to lactate in proliferating tissues?

LDHA (Lactate Dehydrogenase A)

What is the main ATP-generating process in normal differentiated cells under oxygen-rich conditions?

Oxidative phosphorylation

Why do cancer cells favor aerobic glycolysis over oxidative phosphorylation?

It allows for rapid ATP production and provides intermediates for biosynthetic pathways needed for cell growth

what metabolic shift occurs when differentiated cells lack oxygen?

They switch from oxidative phosphorylation to anaerobic glycolysis producing lactate.

What is the role of the PDH (pyruvate dehydrogenase) complex in metabolism?

It directs pyruvate into the mitochondria for oxidative phosphorylation in oxygen-rich conditions.

gene: ALK associated neoplasm

lung adenocarcinoma

gene: EGFR (ERBB1) associated neoplasm

lung adenocarcinoma

gene: HER2 (ERBB2) associated neoplasm:

breast

Gene: HER2 (ERBB2) Associated neoplasm:

Breast

gene: BRAF associated neoplasm

colorectal

Gene: KRAS assocaited neoplasm

colorectal and lung

Oncoproteins

Signal pathways that drive cell proliferation

Growth Factors & Oncoproteins

Growth factors promote cell growth and division

Growth Factor Receptors

Growth factor receptors trigger signaling pathways for cell proliferation

Loss of TP53 Function

Prevents upregulation of PUMA (pro-apoptotic protein), allowing cells to survive DNA damage

BCL2 Overexpression

Overexpression of anti-apoptotic BCL2 family proteins protects tumor cells from apoptosis

Evasion of Cell Death in Tumors

Loss of TP53 + BCL2 overexpression help tumor cells avoid apoptosis

What is the role of growth factor receptors in cell signaling?

activate intracellular signaling pathways that promote cell growth, metabolism, and survival

Tumor Markers

Increased levels of tumor markers can indicate cancer presence

CA15-3/CA27-29

Important markers for breast cancer

CEA

Important marker for colorectal cancer

PSA

Important marker for prostate cancer

Molecular Profiles of Tumors

DNA sequencing has greatly impacted cancer evaluation

RNA Sequencing in Cancer

Widely used in research laboratories for cancer studies

Advances in Cancer Genomics

Enables systematic sequencing and cataloging of genomic alterations in cancers

Impact Zones of Molecular Profiling

Research 🔹 Targeted therapies

General Characteristics of Tumors

Parenchyma (neoplastic cells) & Reactive stroma (non-neoplastic)

Benign Leiomyoma

Small, well demarcated

Slow growing, non-invasive

Non-metastatic, well-differentiated

Malignant Leiomyosarcoma

Large, poorly demarcated
🔹 Rapidly growing, with hemorrhage and necrosis
🔹 Locally invasive, metastatic
🔹 Poorly differentiated

Local Invasions

nearly all bening tumors grow massses that remain localized to their site of origin and lack the capacity to invade distant sites

Metastasis

spread of a tumor to sites that are physically discontinuous with the primary tumor

Morphological changes- differentiation

extend to which. neoplastic parenchymal cell resemble the corresponding parenchymal cells

morphological anaplasia

lack of differentaition

steps of morphological changes

1. Normal cells)) no invasion all normal the epithelial layer (2 capas), basement membrane and below the blood or lymphatic vessel

2. Dysplasia)) REVERSIBLE cells can go back to normal only impact slightly the epithelial cell layer (2 capas)

3. Carcinoma in situ)) disrupts the Epithelium cell layer only pelotita

4. Invasive carcinoma )) invades the epithelial cell layer (2 capas) and the basement membrane

5. Metastasis)) has invaded the epithelial cell layer (2 capas), and basement membrane and invaded the blood or lymphatic vessel