Neoplasia & Oncology

Neoplasia & Oncology

Cancer is a collection of highly-complicated disorders that share the common feature of uncontrolled cell
growth/proliferation (but each type is distinct from each other).
Any malignant tumour or neoplasm with certain characteristics
All caused by accumulation of mutations with influences by environmental factors

EPIDEMIOLOGY
Incidence rates in AUS
Males Prostate (1st, often in older men)
Females Breast (1st, often in younger women)
Both genders Colorectal (2nd), Melanoma (Skin; 3rd), Lung (4th)
Mortality rates in AUS
Males Lung (1st), Prostate (2nd), Colorectal (3rd)
Females Lung (1st), Breast (2nd), Colorectal (3rd)

RISK FACTORS HOST & ENVIRONMENTAL FACTORS

Heredity genetic predisposition to cancer (the most significant risk factor)

Advanced age
Hormone exogenous testerone, steroid therapy, hormone replacement therapy in post-menopause etc
Immunologic chronic inflammation
Obesity
Chemical carcinogens cigarette smoking, diet, alcohol, radiation etc

NORMAL CELL PROCESS PHYSIOLOGY

A number of cells grow & differentiate throughout life, such as epithelial cells (of lungs & colon) and
precursors of the immune system. Stem cells produce large numbers of progeny to repopulate these tissues.
New cells eventually stop dividing and terminally differentiate into a cell type.
Progression through cell cycle is tightly regulated, involving several phases & checkpoints (refer to Figure 1).

Figure 1: Normal Cell Cycle1

http://home.comcast.net/~clupold96/images/notes/mitosis/cell_cycle_graphic.gif

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Checkpoints between each phase prevent cells with any damage or change from propagating in the body.
Cyclins and cyclin-dependent kinases are the key components at these checkpoints. Under the normal
conditions, cell cycle either: fixes the problem (such as damage to genome or cell cycle machinery) then
progress to the next phase; OR arrests and undergoes apoptosis (if unable to fix the problem).
Not surprisingly, the rate & status of cell division is different between tissue/cell types:
a) Labile cells continually dividing & replaced (e.g. skin, oral cavity, GIT, vagina etc)
b) Quiescent cells low level of cell division but can undergo burst of rapid cell division (e.g. liver, kidney,
pancreas); mostly in G0 phase, but can progress to G1 phase (e.g. think about hepatic hyperplasia after loss
of liver masses)
c) Permanent cells non-dividing cells which are arrested in G0 phase for the course of lifespan (e.g.
nervous tissue, cardiac & skeletal muscle etc)

NEOPLASIA DEFINING THE CANCER

Neoplasia or Cancer is a disorder of cell proliferation, differentiation and death.
Initially, the event(s), such as genetic mutations, lead to dysplasia. Altered a cell growth & differentiation
progresses and eventually leads to neoplasia (refer to Figure 2).

Figure 2: Progression of dysplasia to neoplasia

Characteristics of Neoplasm/Tumour
Uncontrolled cell proliferation
Uncontrolled cell differentiation
Uncontrolled apoptosis

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Types of Neoplasm/Tumour
= depend on their secondary characteristics (refer to Table 1).

Table 1: Distinguishing characteristics of benign and malignant neoplasms (Dr Chris DV 2014, p. 5)
Benign Tumours (aka lumps)
may progress to neoplasms
Slow growing
Normal in structure (well-differentiated)
Adherent cells & well-encapsulated by a layer of connective tissue (thus, low risk of invasion & metastasis)
No invasion of local tissue
No metastasis to other tissues
Easy to remove surgically & Generally not recur
Often asymptomatic (but symptomatic when grow large enough to compress other tissues/orgrans)
Malignant Tumours (true cancer)
Cancerous, consists of different cell/tissue structures
More rapid growth rates
Alterations in microscopic appearance (with distinguishable features)
Hallmarks2 anaplasia, nuclear irregularities, loss of normal tissue structure
Not encapsulated
Non-adherent = shed to local areas & systemic circulation
Less contact inhibition
Invasive & metastasise (as Not encapsulated, Non-adherent, & less contact inhibition)
lead to secondary tumour (metastasis) = difficult to remove surgically
Types Solid (in tissues) & Haematologic (involve blood-forming cells)

This part will be discussed in details later

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Tumour Cell Characteristics

= mostly arise from labile cells (esp. epithelial cells) due to continuous cell division (i.e., susceptible to errors)

Abnormal & rapid proliferation

Anaplasia (loss of differentitation) No specialised organisation & functions
Pleomorphism Variations in size and/or shape
Aneuploidy Abnormal number of chromosomes
Phenotypic characteristics genetic instability, growth factor independence, cell density-dependent
inhibition, cell cohesiveness, cell-to-cell communication, autonomy/immortality, antigen expression

Tumour Nomenclature
= named according to the cell type of origin (refer to Table 2), but some named for historical reasons (e.g.
Hodgkins disease).

EXAMPLES OF TUMOUR NONMENCLATURE

CELL/TISSUE
ORIGIN
Carcinomas
Endothelial & epithelial tissues
Sarcomas
Connective tissues
Adenoma
Glandular or ductal epithelium (BENIGN)
Adrenocarcinoma Glandular or ductal epithelium (CARCINOMA)
TeratoGerm cells
Table 2: Examples of Tumour Nomenclature (modified from Table 36-2, Craft et al. 2012).

PATHOPHYSIOLOGY NEOPLASIA MECHANISMS & THEORIES

Neoplasia or Cancer is fundamentally a genetic disorder that arises due to abnormalities/mutations in genes.
However, the process can also be altered or influenced by environmental factors.

Abnormal Cell Growth in Neoplasia

Under normal conditions, cell growth regulation is controlled by extracellular & cellular molecules. Cellular
molecules (growth factors & growth inhibitors) bind to target receptors on cells, inducing signal transduction.
Signal transduction initiated by growth factor eventually activates protein for cell growth & division. On the
other hand, signal transduction initiated by growth inhibitor activates synthesis/release of inhibitory proteins.
As you may know of or expected, this progress is altered in tumour cells. Abnormal proliferations of tumour
cells are due to autocrine stimulation (secreting growth factors for self-growth stimulation) and increase in
number of growth hormone receptors (so called receptor upregulation) on tumour cell membranes. Apoptosis
is disabled in tumour cells, and hence they acquire autonomy in the body.

Genes Altered in Cancer

Mutations can be due to errors in DNA replication or environmental (& lifestyle) causes. Occasionally,
dividing cells deviate from normal genetic program, but sophisticated multilayer defences prevent proliferation
of these cells.

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In cancer, mutations most commonly occur in two types/classes of gene:
Tumour-suppressor gene inactivated in cancer
Proto-oncogenes activated in cancer
These genes, like any other genes, have two chromosomal alleles inherited one from each parent. Therefore,
inactivation/activation of these genes (which occur in cancer) requires two-hit mutations (refer to Figure 3).

Figure 3: Genetic Mutation in Cancer

The first copy (allele) is often inactivated by point mutations or as inherited from one parent. At this point of
time, individuals are susceptible to development of neoplasms.
Tumour suppressor gene is a gene which encodes proteins that suppress cancer development. This gene is
normally found in cells as they suppress uncontrolled cell proliferation in our body (by slowing the cell cycle,
inhibiting proliferation from growth signals, and arresting cell division when cell is damaged).When this gene
is mutated, it loses its inhibitory function against uncontrolled cell proliferation. As you may have expected,
this type of mutation results in lack of tumour-suppressing function, which in turns causes a number of tumours
(refer to Table 3).

TUMOUR CAUSED BY TUMOUR-SUPPRESOR GENE FUNCTION LOSS

GENE
SYNDROME
p16INK4a, CDK4 Familial melanoma
APC
Familial adenomatous polyposis (colorectal cancer)
BRCA1, BRCA2 Breast cancer
Table 3: Examples of Tumour Nomenclature (modified from Table 36-3, Craft et al. 2012).

Proto-oncogenes normally stimulate cell proliferation, and involved in normal regulation of cell growth (such
as growth factors, growth factor repressors, signal transduction molecules, and nuclear transcription factors)
Mutations in these genes can result in either: hyperactive form or inappropriate regulation. As this type of
mutation promotes development of cancer, a mutation in a proto-oncogene can become oncogene (meaning
cancer-inducing gene).
Oncogenes are mutant genes that stimulate unregulated cell proliferation. Most common genetic event that
activates oncogenes is point mutation (a mutation in check points of the cell cycle). Point mutations are small
changes in DNA which affect the activity of proteins (i.e., increasing activity of oncogenes). As discussed
previously, oncogenes originate from proto-oncogenes.