Lecture 2 : Historical Perspectives in Cancer

Cancer: no. 1 cause of death in the western world

50K cancer deaths in Australia estimated for 2022

• 1/2 men and 1/3 women will be diagnosed with cancer by 85 and
>400K people living with cancer (https://canceraustralia.gov.au/)

“Civilisation did not cause cancer but by

extending human life span unveiled it”

Siddhartha Mukherjee (oncologist)

 Overview of lecture

Palaeo-Oncology: Cancer in Fossil record >240

million years
Ancient Egypt 3000-1500 BCE
Ancient Greece 700-100 BCE
Ancient Rome 50 BCE-450 AD
Middle Ages 5th -15th century
Renaissance 14th -17th century
Age of reason/Enlightenment 17th-18th Century
The 19th century emergence of scienti c
oncology
Emerging understanding of cancer causes
Development of core treatments - surgery,
radiotherapy and chemotherapy
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 Overview of lecture

Palaeo-Oncology: Cancer in Fossil record >240

million years
Ancient Egypt 3000-1500 BCE
Ancient Greece 700-100 BCE
Ancient Rome 50 BCE-450 AD
Middle Ages 5th -15th century
Renaissance 14th -17th century
Age of reason/Enlightenment 17th-18th Century
The 19th century emergence of scienti c
oncology
Emerging understanding of cancer causes
Development of core treatments - surgery,
radiotherapy and chemotherapy
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Palaeo-Oncology: Cancer in Fossil record

Paleopathologic findings of 240 million-year-

old turtle bone revealed tumours in triassic
dinosaurs

Cancer (osteosarcoma) in 1.7 million year fossil

bones for human relative Australopithecus
sediba in Swartkrans Cave (South Africa)

Vulnerability to mutation deeply rooted in the

DNA code
 Oldest cancer in modern humans 2300 BCE
CT scans of ancient Egyptian mummies oldest evidence of women with
breast cancer and men with prostate cancer (2300 BCE >4300 years old)

Oldest known case of metastasising prostate carcinoma diagnosed in

skeleton of 2,700‐year‐old Scythian king (Siberia)

Yet most ancient texts have little to offer on the malady?

Our ancestors tended
to die young……lucky
to survive the pox or
the plague!!
 First written evidence of cancer knowledge

Ancient Egypt 3000-1500 BCE

2625 BC: Edwin Smith Papyrus earliest medical

text with description of cancer “breast cancer:
disease of the breast without a cure.”

1550 BC: Ebers Papyrus cancer treatment:

recounting a "tumour against the god Xenus" it
recommends "do thou nothing there against”
Edwin Smith Papyrus

Blamed Cancer on the Gods!!

Also “Clothing: may be

protected from mice and
rats by applying cat's fat”

Ebers Papyrus
Also first evidence of cancer treatment with surgery and chemicals

Removal of cancers via surgery with

cautery knives

Also used salts, spices and arsenic

paste “Egyptian ointment” as early
chemical therapy i.e. chemotherapy

Egyptian medical tools Egyptian spices

Arsenic deadly poison or cancer cure??

Arsenic was also used in Chinese medicine

In Western medicine >60 di erent arsenic

preparations have been developed and used in
pharmacological history

Recent successful clinical trials using arsenic

compounds for cancer treatment

Food and Drug Administration (FDA) has approved

Arsenic trioxide (Trisenox) for current cancer
treatment
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Arsenic lethal for rats but gentle on skin!!
Arsenic lethal for rats but gentle on skin!!
Arsenic lethal for rats but gentle on skin!!
 Ancient Greece 700-100 BCE
Hippocrates opposed superstitious causes
of cancer
Cancer is initiated by natural causes
(Humoral theory) e.g. excess or depleted
blood, mucus, bile, other body secretions.
Coined the terms karkinos (carcinos) and Hippocrates (460-375 BCE)
Greek Physician
carcinoma to describe non-ulcer and ulcer-
forming tumours
Greek karkinos = crab 🦀
Most likely because of the finger-like
spreading projections from a cancer
 Ancient Rome 50 BCE-450 AD

Aulus Celsus (25 BC-AD 50) best source of

medical/cancer knowledge in Roman world
made Latin the language of medicine -
karkinos became cancer i.e. latin for crab 🦀

De Medicina (1478 AD) recommended

aggressive surgical therapy for cancer
Aulus Celsus “De Medicina”
Ancient Rome 50 BCE-450 AD

Claudius Galen (130-200 AD) Greek

Physician practiced medicine in Rome

Prolific writer - more than 100 notes

on tumours and cancers

Adopted Hippocrates Humoral theory:

black bile caused incurable cancer
and yellow bile caused curable cancer Claudius Galen

Coined the word oncos (Greek for

swelling) to describe tumours

Against surgical treatment of cancer

Set cancer treatment back centuries!!

Humoral theory
Adherence to humeral theory delayed advances in cancer
treatment for centuries…blood letting did not help!!
 Middle Ages 5th -15th century
Henri de Mondeville (1260-1320) Medieval French Anatomist and
Surgeon. Publicly rejected 1000-year-old Humoral theories

He classified cancers: simple or compound basis on a history of

prior lesions; size; anatomic site; superficial or deep in location

Proposed external carcinogens enter the body via orifices or glands

 Middle Ages 5th -15th centuries
John Arderne (1307-1390) Operated guided by human anatomy and
excised cancer at early stages by knife
Made anaesthetic out of hemlock, henbane, and opium to ease pain
Arderne helped rich and the poor alike…..rich men should be charged
as much as possible, but poor men should be remedied free of charge

John Arderne (1307-1390)

London Surgeon General
Founder of Modern Surgery
 Renaissance 14th -17th century
Antonio Benivieni printed the first pathologic anatomic work and
case report of a cancer in his book De Abditis (1507)
First description of carcinoma of pyloric part of stomach
"Father of pathological anatomy” as rst to compare pathological
anatomical and clinical data
Benivieni’s protocols similar to those used in autopsies today

Antonio Benivieni
Florence (1443-1502)
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Renaissance 14th -17th century

Paracelsus: Pioneer in chemistry and

chemotherapy

Studied actions of poisons through

experimentation and introduced
concept of dose - theorised materials
poisonous in large doses may be
curative in small doses

Introduced mercury, lead, sulphur, zinc, Paracelsus (1493-1541)

Swiss physician-chemist
copper, arsenic, iodine, and potassium
as internal remedies

Traveled Europe promoting his

remedies but annoyed establishment
opponents who murdered him in
Salzburg, Austria.
 Enlightenment 17th-18th Century

Francis Bacon (1561 – 1626) Isaac Newton (1642 – 1726)

Developed the scienti c method Foundations of classical physics
seminal contributions to optics

Key figures in the 17th Century “Scientific revolution”

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 Invention of microscopy and cell theory

Antonie Leeuwenhoek (1632–1723)

Father of microbiology
Invented single-lensed microscopes

Microbes called animalcules (Latin =“tiny animal")

 Invention of microscopy and cell theory

Robert Hooke (1635 – 1703)

Natural philosopher, architect, polymath
Father of cell theory of biology

Invented Compound microscope of style still used today Cork Cells

Hooke "By the means of Telescopes, there is nothing

so far distant but may be represented to our view;
and by the help of Microscopes, there is nothing so
small as to escape our inquiry; hence there is a new
visible World discovered to the understanding”
 Cancer at the end of the 18th Century
Ominous lesion that spreads destructively and is fatal if left untreated

Prone to recur after excision, either locally or at distant site

Still believed in “Humoral, Lymph, Blastema, irritation, trauma,

infectious disease” theories of the origin cancer

Disciplines of Microscopic Pathology and Surgical Oncology arose

Invasive Breast Carcinoma Surgical Oncology

The 19th century emergence of scienti c oncology

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 Extension of cell theory to animal and human tissues
1. The cell is the unit of structure, physiology, and
organisation in living things

2. The cell retains a dual existence as a distinct entity

and a building block in the construction of organisms

Theodor Schwann (1810-1882)

German physician-physiologist
 Cancer originated from special cells called “blastema”

Prussian oncologist Johannes Muller (1838): cancer made

of cells not lymph. Arises by spontaneous generation in
bodily fluids from 'blastema' budding elements between
undifferentiated tissue that also gave rise to normal cells

French gynaecologist Joseph Recamier (1829) - Cancer

formed by new cells in diseased organs and spread to Johannes Muller
other parts of the body by vascular invasion or metastasis

Metastasis = tumour spreading Joseph Recamier Cancer made up of cells

 Cellular origin of Cancer
Rudolph Virchow (Muller’s student) determined all
cells, EVEN cancer cells, derived from other cells

Virchow’s “All cells come from cells” realisation

ended the 2000-year-old humoral and 100-year-
old lymph theories for cancer origin

Every pathologic lesion consists of cells

derived from pre-existing cells Rudolph Virchow (1821-1902)
Prussian pathologist
Cancer Causes 18th-20th Century
 Occupational/environmental Cancer
Percival Pott (1714- 1788) first scientist to identify
a cancer caused by environmental carcinogens

Chronic exposure to soot caused scrotal

carcinoma in chimney-sweeps - mainly kids

Pott's "Chirurgical Observations" a framework

for modern Occupational cancer studies Percivall Pott
English surgeon
Carcinogens (chemicals) causing cancer
1930: Ernest L. Kennaway (London) isolated
polycyclic hydrocarbons from coal tar and
demonstrated carcinogenic in experimental animals

1941: 95% of lung cancers occurred in smokers,

but not until 1964!! that Surgeon General (USA)
announced cigarette smoking causes lung cancer

1940-50: >300 compounds identified as

carcinogenic by the National Cancer Institute (USA)
Smoking causes cancer
Anti-smoking campaign reduced US cancer deaths

Men Women

Cancer death rates US,1930-2009

 Cancer caused by tissue damage and disease
squamous carcinoma of tongue to leukoplakia
mucosal or cutaneous cancers to inflammatory,
mechanical, and chemical irritations
melanoma to sun traumatised nevi
malignant tumours of the thyroid to goitres Normal mole

colon cancer to ulcerative colitis

liver carcinoma to cirrhosis of the liver
gastric carcinoma to stomach ulcer

Malignant mole

Normal liver

Normal thyroid Goitre

Liver cirrhosis Ulcerative colitis Normal colon
 Viruses linked to cancer

1910: Peyton Rous (1879-1970) pathologist at the Rockefeller

Institute for Medical Research, demonstrated sarcoma in hens could
be transmitted by injection of cell-free filtrates to other hens
The sarcoma-causing agent: an RNA group sarcoma virus
Led to identi cation of human cancer causing genes (oncogenes)
including SRC, MYC, Ras (More in Lecture 4)

Rous’s Chicken Rous sarcoma virus Infecting virus

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 Bacterial infection major cause of stomach cancer
1984: Australian gastroenterologist Barry
Marshall (1951-), and pathologist J. Robin
Warren (1937-) reported Helicobacter pylori in
biopsies from most patients with gastric or
duodenal ulcers
Marshall infected himself with Helicobactor to
demonstrate ulcers caused by the infection!!! Marshall & Warren
Nobel Prize 2005
50% of the world's population carried the
organism putting them at major risk for gastric
carcinoma in chronically infected individuals H. pylori

Helicobacter pylori H. pylori infection gastric ulcers

 Antibiotics to kill H. Pylori decreased stomach cancer death
Cancer death rates by type, World
Age-standardized death rates across cancer types, measured as the number of deaths per 100,000 individuals.
Age-standardization assumes a constant population age & structure to allow for comparisons between countries
and with time without the effects of a changing age distribution within a population (e.g. aging).

25
Tracheal, bronchus, and lung cancer

20
Colon and rectum cancer
Stomach cancer
Liver cancer
Breast cancer
15 Pancreatic cancer
Prostate cancer
Esophageal cancer
Cervical cancer
Brain and nervous system cancer
Bladder cancer
10
Lip and oral cavity cancer
Gallbladder and biliary tract cancer
Ovarian cancer
Kidney cancer
Larynx cancer
5 Other pharynx cancer
Uterine cancer
Nasopharynx cancer
Non-melanoma skin cancer
Thyroid cancer
0 Testicular cancer
1990 1995 2000 2005 2010 2017
?
?
 Genetic Causes of Cancer
Familial cancer: significance cancer
heredity not fully appreciated until Lynch
syndrome described in 1966

Other hereditary cancer syndromes include:

Retinoblastoma
multiple polyposis of the colon
neurofibromatosis
nevoid basal cell carcinoma syndrome Lynch syndrome
Li-Fraumeni syndrome
Some breast and ovarian cancers

Neurofibromatosis Retinoblastoma
 Single Gene Causes of Cancer Identified
1979 Tumour suppressor TP53: most commonly mutated gene in cancer

1986 HER2 oncogene found in breast cancers led to HER inhibitor drugs
in clinic in 90s - still first line therapy

1994/5 Tumour suppressor genes BRCA1/2 identified (carriers have 85%

higher breast and ~45% ovarian carcinoma risk)
Cancer Treatment 19th-20th Century
 19th Century Advances in surgery
Improved anaesthesia and antiseptic techniques lead to more radical
operative procedures and novel methods for cancer surgery

In 1889 Karl Pawlik, gynaecologist, developed the endoscope and

performed the first cystectomy (bladder removal) in cancer patient
(Prague)

1892 Howard Atwood Kelly independent method of endoscopy (America)

Endoscope: removal of bladder tumours with transurethral catheters

and forceps decreased mortality rates
 Radical Mastectomy increases breast cancer survival

Early breast cancer surgery was extraordinarily painful and usually fatal
1891: Baltimore surgeon William Halsted introduced radical
mastectomy as believed if tissue was removed in small pieces could
spread cancer cells into the wound
Halsted technique removed the pectoral muscles, axillary nodes and
all breast tissue in one large section
A truly brutal procedure, but it worked….the 5 year survival rate
increased from 0 to 40 %
 Development of Cancer Radiotherapy

Wilhelm C. Rontgen (1845-1923) a German

physicist, accidentally discovered rays: x-rays
led to first radiation therapy

1897: x-ray radiation introduced for

treatment of inoperable breast cancer

Antoine H. Becquerel (1852-1908) and Marie

Curie (1867-1934) discovered radioactivity of
uranium and treatment with radium was
rapidly introduced for skin cancers

New York surgeon Robert Abbe (1851-1928)

successfully used radiation to treat
squamous carcinoma

Radiotherapy is still a core cancer treatment

 Origins of 20th century chemotherapy

Mustard gas: from the Great War to frontline chemotherapy

1919: Edward Krumghaar reported “severe depletion of bone marrow

elements in soldiers exposed to mustard gas in WWI

1942: Louis Goodman and Alfred Gilman demonstrated mustard gas

therapy also destroyed cancerous cells in a lymphoma patient

1948: Alexander Haddow identi ed mustard molecule killing cancer cells

- structure similar to chlorambucil still used to treat leukaemia

Monumental moment in medical history beginning chemotherapy era

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 Development of broad spectrum Chemotherapy
Sidney Farber (1903-1973) paediatric pathologist demonstrated
temporary remission of leukaemia in children treated with folic acid
antagonist aminopterin (1948: Boston)
1960: reported relapse-free survival in children with Wilms' tumour after
actinomycin D treatment. Still a rst line therapy for these kidney
tumours and also rhabdomyosarcoma, Ewing's sarcoma, trophoblastic
neoplasm, testicular cancer, and ovarian cancer.
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 1971 WAR on Cancer!!
$500 billion in 2012 dollars has been spent since Richard Nixon
declared “war on cancer” in 1971 (The National Cancer Act)
The US is winning the WAR for some cancers….
The WAR on cancer is far from over!
 Second WAR on Cancer!!
2016 Congress passed 21st Century Cures Act - $1.8 billion
(over 7 years) for Joe Biden’s Cancer Moonshot proposal

Time will tell…..

 Summary
Cancer not a new disease - increased incidence with ageing populations

Cancer is a genetic disease, but also depends on infectious diseases,

environment, and/or tissue damage

Surgery, radiation and chemotherapy remain the mainstay of treatment

Future looks to: further prevention, early detection & targeted therapy
We will address 21st Century progress in cancer therapy

Built on our understanding of cell and molecular biology

 Targeted chemotherapy
Until 1991 the majority of treatments for cancer were one-size-
fits-all approaches that emphasised cytotoxic chemotherapy
Recent cancer drugs targeted to the Cancer Hallmarks
Cancer genomics has led to the idea of personalised, precision
and stratified medicine “Right drug, right patient, right time”