Cancer: Types, Tumors, and Cell Growth

Cancer Overview

• Cancer is characterized by the uncontrolled proliferation of abnormal cells.
• These cells can invade, destroy healthy tissue, and spread throughout the body.
• Cancer can affect any organ and often results from a combination of factors, including environmental exposures.

Defining Cancer

• Cancer involves malignant diseases with increased anarchic and abnormally large cells in the body.
• Cancer cells proliferate endlessly and form masses called tumors.

Tumors Explained

• Benign tumors are noncancerous and rarely cause serious problems unless they appear in a vital organ, grow very large, or put pressure on surrounding tissues.
• Benign tumors grow slowly, stay in one place, and don't spread and typically do not reappear after surgical removal.
• Malignant tumors are cancerous and can originate in any of the body's millions of cells.
• Malignant tumor size and shape vary; they grow uncontrolled, invade nearby tissues, blood vessels, or lymph vessels.
• Malignant tumors interfere with bodily functions, endangering safety.

Malignant Cancer and Metastasis

• Malignant cancer cells can detach from the original tumor and spread to distant sites, this process is called metastasis.
• Cancer that spreads from its original location to a new area of the body is metastatic cancer.
• Malignant tumors can also reappear after treatment, known as recurrence.

Breast Cancer Staging

• Breast cancer is classified by stages of development, which determine treatment choices and provide a better understanding of prognosis.
• Stage 0 involves atypical cells in breast tissue without any sign of spread to the lymph nodes.
• Stage 1 includes a tumor size of less than 2 cm. without spread to surrounding lymph nodes or outside the chest.
• Stage 2 is divided into two categories based on tumor size and lymph node spread.
• Stage 2A: tumor is less than 2 cm and affects lymph nodes, or the tumor is 2-5 cm without auxiliary lymph breach.
• Stage 2B: the tumor is more than 5 cm and auxiliary lymph nodes are negative for cancer, or the tumor is 2-5 cm with axillary lymph node involvement.
• Stage 3 is divided into two categories.
• Stage 3A: the tumor is more than 5 cm with spread to lymph nodes, or any size tumor with lymph node metastases attached to surrounding tissues.
• Stage 3B: any size tumor with metastases in skin, muscles, or mammary gland internal
• Stage 4 is determined by cancer spread to other organs or tissues, e.g., liver, lungs, brain, skeletal system, or lymph nodes near the collarbone.

IARC Carcinogen Classification

• Interdisciplinary working groups of international scientific experts review published studies and assess the evidence of carcinogenicity.
• IARC examines the possible carcinogenicity of chemicals, complex mixtures, occupational exposures, physical and biological agents, and behavioral factors.
• Bradford Hill criteria are used in this classification.

IARC Carcinogen Groups

• IARC defines four groups (1 to 4) based on how likely something is to cause cancer in humans.
• Group 1: Carcinogenic to humans.
• Group 2A: Probably carcinogenic.
• Group 2B: Possibly carcinogenic.
• Group 3: Unclassifiable agent regarding carcinogenicity.
• Group 4: Agent probably not carcinogenic.

Establishing Causality

• Scientists aim to establish causality between environmental exposures and cancer risk.
• This is done by gathering arguments based on the Bradford Hill criteria.

Sir Austin Bradford Hill

• Sir Austin Bradford Hill was a medical statistician whose work included "Principles of Medical Statistics 1937".
• He conducted the First Randomized Clinical trial, and researched Smoking and Lung Cancer
• He gave an Address to the Royal Society of Medicine in 1965 as president of the newly founded Occupational Medicine Section

Context for Causation

• Statements about causes are needed to motivate action to protect public health.
• This is mentioned in Smoking and health: Report of the Advisory Committee to the Surgeon General, 1964

Strength of Association

• The strength of association measures the difference in effects between exposed and unexposed groups.
• A stronger association means causation is more likely.
• Undetected bias can make weak associations spurious.
• The strength of association is measured by risk ratio, relative risk, odds ratio, or regression coefficient, not the p-value.

Consistency in Research

• Consistency requires repeated observation of association by different persons, in different places, circumstances, and times.
• Hill suggested that consistency may only cut one way.
• Consistency supports causality, but the absence of consistency may not undermine causality.
• An example of when a single exposure group is sufficient.

Specificity in Causation

• A specific outcome closely tied to a specific exposure suggests a direct relationship and is less likely to have other actors at play.

Temporality

• Temporality means the cause must precede the effect, which is an absolute requirement.
• Difficulties can arise when interpreting data retrospectively or when the timing of exposure is unclear.
• The consistency of the time interval can be relevant.

Terminology of disease

• Induction period characterizes the relationship between the onset of causal action and the onset of disease.
• Latency period is the period without clinical symptoms between onset of disease and the onset of clinical symptoms.

Biological Gradient

• Dose response relationships are important in understanding biological gradients.
• Linear relationships are useful, but there are other possibilities like threshold effects and non-linear processes.
• Finding a satisfactory quantitative measure of the environment to explore the dose response is a difficulty.

Plausibility

• Biological plausibility asks if there is a biological mechanism that explains the effect.
• Defining criteria for plausibility is difficult.
• Any relation can be described as plausible once an association is observed.

IARC's 10 Key Characteristics of Human Carcinogens

• Established human carcinogens commonly exhibit one or more of these characteristics.
• Data on these characteristics provide evidence of carcinogenicity and help interpret the relevance and importance of findings of cancer in animals and humans.
• The key characteristics include:
  • Being electrophilic or capable of being metabolically activated.
  • Being genotoxic.
  • Altering DNA repair or causing genomic instability.
  • Inducing epigenetic alterations.
  • Inducing oxidative stress.
  • Inducing chronic inflammation.
  • Being immunosuppressive.
  • Modulating receptor-mediated effects.
  • Causing immortalization.
  • Altering cell proliferation, cell death, or nutrient supply.

How Carcinogens Work

• Carcinogens can work in many ways.
• They produce compounds/metabolites with electrophilic structures or causing the formation of DNA and protein adducts.
• They cause DNA damage (strand breaks, cross-links, unscheduled synthesis), intercalation, mutations, and cytogenetic changes.
• They alter DNA replication/repair or modifying DNA methylation/histones/microRNA expression or inducing oxygen radicals.
• Carcinogens can induce elevated white blood cells and alter cytokine or chemokine production
• Some examples of carcinogens are Decreased immunosurveillance, immune system dysfunction
• Modulating receptors - e.g Receptor in/activation or modulation of endogenous ligands hormones
• Carcinogens can cause Inhibition of senescence and alter telomeres
• Growth - e.g increased or decreased cellular replication, changes in growth factors, energetics, and signaling pathways related to cellular replication or cell cycle control and angiogenesis

Coherence

• A good interpretation should not conflict with generally known facts
• The data should match the current understanding of biological processes
• It's helpful if results agree with toxicological results and is important for peer reviews

Experimentation

• Studying the Impact of Preventative Action is part of experimentation
• Lower lung cancer rates caused by a reduction in smoking rates
• Analyzing birth weights of pregnancies that overlapped with the Beijing Olympics.
• It's important to consider biases in intervention studies

Bradford Hill's Analogy

• This viewpoint is often dismissed or altered
• Some texts use the term, “consideration of alternate explanations”
• "With the effects of thalidomide and rubella before us we would surely be ready to accept slighter but similar evidence with another drug or another viral disease in pregnancy.”
• Rubella and thalidomide were recognised as teratogens in 1949 and 1961
• These examples can be compared to the precautionary principle.

Criticisms of Bradford Hill's Criteria

• Individual guidelines are not absolutely necessary for determining whether something causes cancer.
• Evaluation of guidelines and evidence is subjective
• Oversimplification of a cause and effect relationship might provide disoriented actions
• Does not address multi-factorial (a lot of things that can cause this effect to happen) causality clearly
• A reason why many guidelines were revised and adapted from the Bradford Hill principles

Modern Applications

• Environmental Regulation (Air Quality requirements, International agency for research on cancer)
• Evaluating a very big amount of data to be able to arrive at a conclusion

Estimating the Amount of Environmentally Related Cancers

• Factors that determine difficultly are Genetic susceptibility, windows of exposure, interactions and transgenerational effects, and multi-exposures

Carcinogenesis

• A carcinogen is an agent that can induce or increase the risk of cancer, alone or in combination of other agents.

Rates

• A rate measures how often an event happens in a specific group over a certain time. For example number of deaths in Canadians out of 100,000 per year