Pathophysiology: Cancer Overview

• Review material for Exam 2, covering Units 3, 7, and 8 for the Pathophysiology N3517 course in Spring 2025. The notes are for class use.

Cancer Overview

• Cancer involves a loss of cellular differentiation, known as anaplasia.
• It lacks a capsule, invades local blood supply, and can create its own blood supply through angiogenesis and spread to other areas.
• Malignant tumors grow rapidly, are not encapsulated, are invasive, poorly differentiated, have a high mitotic index, and can spread distantly (metastasis).
• Benign tumors grow slowly, have a well-defined capsule, are not invasive, are well-differentiated, have a low mitotic index, and do not metastasize.
• Carcinoma in situ (CIS) represents early-stage, preinvasive tumors of glandular or squamous cell origin that have not broken through the basement membrane.
• CIS can remain stable, progress to invasive and metastatic cancers, or regress and disappear.

Human Carcinogenesis

• Key genetic mechanisms in carcinogenesis include the activation of proto-oncogenes, resulting in hyperactivity of growth-related gene products which are called oncogenes.
• Mutation of genes results in loss/inactivity of tumor-suppressor genes, which normally inhibit growth.
• Mutation of genes leads to overexpression of products that prevent normal cell death (apoptosis), allowing continued tumor growth.

Proto-oncogenes, Oncogenes, and Tumor Suppressor Genes

• Proto-oncogenes are normal, non-mutant genes coding for cellular growth.
• Oncogenes are mutant genes directing protein synthesis and cellular growth.
• Tumor-suppressor genes encode proteins that negatively regulate proliferation and are also referred to as anti-oncogenes.

Sustained Proliferative Signaling (Hallmark 1)

• Cancer cells exhibit uncontrolled cellular proliferation, responding to growth factors, expressing mutated proto-oncogenes (oncogenes), leading to uncontrolled sustained proliferation.
• Autocrine stimulation enables cancer cells to secrete growth factors that stimulate their own growth.

Mutation of Normal Genes

• Point mutations, such as changes in nucleotide base pairs; can convert a regulated proto-oncogene to an unregulated oncogene, accelerating growth.
• Chromosome translocation involves the transfer of a piece of one chromosome to another.
• Gene amplification duplicates a small piece of a chromosome over and over, resulting in the increased expression of an oncogene.

Genomic Instability (Hallmark 3)

• Cancer cells show increased mutations and alterations in the genome.
• Caretaker genes involved in DNA repair are decreased.
• Chromosome instability is increased in malignant cells, resulting in chromosome loss, loss of heterozygosity, and chromosome amplification.

Enabling Replication Immortality (Hallmark 4)

• Body cells are not immortal and can only divide a limited number of times, but cancer cells activate and sustain telomerase.
• Telomeres, protective caps on chromosomes held by telomerase, become smaller with each cell division, signaling cells to stop replication.
• Telomerase activity preserves telomeres on cancer cell chromosomes, enabling continued replication.

Genetics and Cancer-Prone Families

• Mutagen exposure and mutation in somatic cells are not transferred to offspring, but in germ cells (germline mutant allele) may be transferred to future generations.
• Tumor suppressor genes are usually involved, such as the Retinoblastoma (RB gene).

Mutation in the p53 gene

• Tumor Associated Macrophages prognosis diminishes cytotoxic response, and producing cytokines that are advantageous for cellular growth and spread
• Hallmark 7: Resistance to Destruction: Mutation in the p53 gene.

Tumor Manipulation

• Tumors manipulate inflammatory and immune responses, promoting cellular proliferation, neovascularization, and local immune suppression through a wound healing phenotype.
• Tumor-associated macrophages (TAMs) promote tumor survival by secreting cytokines, which lead to monos into tumor into macros. This causes anti-inflammatory (healing) macro phenotype.
• TAM secrete cellular growth factors leading to tumor growth and invasion.

HPV & Cervical Cancer

• HPV is implicated in cervical cancer detection, and is identified through Pap tests. Vaccines exist against common oncogenic HPV types.
• HPV 16 & 18 are responsible for 70% of cervical cancers, while HPV 6 & 11 cause 90% of genital warts.

Activating Invasion and Metastasis (Hallmark 8)

• Metastasis: the spread of cancer from a primary site of origin to a distant site, this involves direct expansion, penetration of vessels, transport, and secondary locations.
• Metastasis often occurs in the first capillary bed encountered by circulating cells, exhibiting organ tropism.

Cancer Epigenetics

• Study of changes in gene expression or cellular phenotype, caused by mechanisms other than changes in the underlying DNA sequence.
• Aberrant methylation silences Tumor Suppressor Genes, antimethylation drugs can act as reversal agent.
• miRNA target gene expression

Environmental and Lifestyle Factors for Cancer

• Obesity is associated with cancers, causing poorer outcomes and affecting genomic stability, dysregulated growth signaling, apoptosis inhibition, immune surveillance, and angiogenesis.
• Physical activity reduces cancer risk, decreases insulin and obesity, inflammatory mediators and free radicals, and increases gut motility.

Staging: Tumor Markers

• Used to screen for cancer that diagnose tumors or observe Hormones/Antigens/Antibodies/Enzymes can be tumor markers
• Staging involves the tumor's size, degree of invasion, and extent of its spread. (World Health Organization TNM system)

TNM systems

• Primary Tumor (T), Regional Lymph Nodes (N), Distant Metastasis (M) Has number to indicate spread

Side Effects of Cancer Treatment

• Gastrointestinal tract
• Bone Marrow
• Hair and Skin
• Reproductive tract

Cardiac Performance

• Preload-- pressure that is full in the heart/end of diastole
• Afterload--Resistance pressure and ejection
• Myocardial contracility and preload is controlled
• Heart rate

Frank-Starling Law

• Stroke heart increases in response to increase of blood volume when constant Increased volume has ventricular heart contration

Regulation of blood pressure

• Blood pressure is determined by cardiac output and peripheral resistance. Cardiac output is influenced by heart rate and stroke volume.
• Peripheral resistance is affected by blood viscosity, vessel diameter, sympathetic nervous activity, and humoral regulation.

Diseases of Arteries and Veins

• Orthostatic hypotension is a decrease in blood pressure upon standing, leading to fainting.
• Treatment involves increasing salt intake, raising the head of the bed, wearing thigh-high stockings, expanding volume with mineralocorticoids, and administering vasoconstrictors.

Primary Hypertension

• Obesity, genetics and dysfunction and environment are causes in the SNS, RAA, and natriuretic hormones. It causes Vasoconstrictionand increased peripheral resistance. Can result in renal or cardiac failure

Aneurysm facts

• Aneurysm is a local dilation of vessel-complications are disection, ischemia or rupture. An aortic aneurysm can be Thoracic vs Abdominal

Atherosclerosis

• Atherosclerosis a plaque in the arterial wall(plaque development)-risk factors are LDL or VLDL-Can cause angina

Coronary Artery Perfusion

• Blood flows into the ventricles through ventricular relation, it prevents backflow

Normal Cardiac Rhythms

• Coronary Artery Disease and normal sinus rhythms are healthy

Coronary Artery Disease

• Transient or temporary deprivation of coronary blood supply leading is transient ischemic. Myocardial ischemia causes is Stable angina/ Silent ischemia or Prinzmetal angina

Myocardial Ischemia

• Myocardial (heart attack): extended obstruction of supply leading to of Troponin and EKG changes. Can have Manifestations pallor, diaphoresis fatigue, EKG changes .There are 3 stages Stable Angina, Unstable and Transiet

Myocardial Ischemia

• Myocardial stunning is Temporary loss of contractility, while the Hibernating myocardium is metabolic adaptation
• EKG Changes and High T elevation occurs: the cellular injury is cellular death: structural and functional changes.

Pericardial Effusion

• Fluid accumulates in pericardial cavity and trauma to neoplams: Can lead to Sudden (pericardial tamponade):

Cardiac Tamponade

• Fluid or blood buildup around the heart altering flow
• JVD, edema, hepatomegaly ↓ stroke volume, ↓ cardiac output

Valvular Dysfunction

• Stenosis causes Hypertrophy, Atypical chest pain, can be Diastolic Murmurs, angina pectoris or Pulmonary edema with dyspnea on exertion.
• Regurgitation- Impaired back-flow can hav e atypical pain and Dyspnea

Endocarditis

Usually Colonization with microbes-Vegetation are blood clot or bacterium

Systolic heart failure

• Is inability of heart to generate adequate cardiac output and EF lower then 40%

Heart Failure

• Diastolic (Pulmonary congestion and pulmonary despite normal stroke volume):
• Right (Fluid backs-up into systemic system. JVD, edema, S3 gallop) Dyspnea, orthopnea, cough, frothy sputum, fatigue edema

Left Heart Failure

Results In the Ejection fraction and Myocardial infarction and low RV output. Results in Hypertension

Left Heart Failure facts

· ↑ PVR · Mitral stenosis · ↓LA emptying ↑ LA preload

Acute Respiratory Distress facts

Fulminant respiratory failure-Diffuse alveolocapillary injury:

Pulmonary cont

Pulmonary artery is vasoconstricted due to PH levels Interstitial fibrosis · COPD 127/234 Restrictive or Obstruction Disease 1.Restrictive pulmonary disorder