Cancer arises from uncontrolled cell growth. Malignant tumors can invade other tissues and spread, while benign tumors remain localized. Cancer stem cell hypothesis suggests that cancers originate from mutated adult stem cells that have lost their normal constraints. Tumor cells resemble embryonic cells in their migration and ability to be influenced by their environment - some tumors can be stopped by inducing differentiation of the cancer cells. Cancer development involves a combination of genetic and epigenetic factors, including mutations in oncogenes and tumor suppressor genes as well as epigenetic changes like DNA methylation that regulate these genes.

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Cancer & Oncogenesis (Tumorigenesis)
Cancer can be defined as the uncontrolled overgrowth of cells. Cancer can be
categorized into two types: (1) Malignant Tumor: This type of cancer invades other
tissues (nearby or even distant), i.e. it does not stay restricted to just one area but
instead spreads to other tissues as well. (2) Benign Tumor: This type of cancer does not
invade other tissues; it stays restricted to just one area.
Cancer & Autocrine Growth Factors:
Cancer cells can synthesize their growth factors and respond to them. For example in
the case of human small cell lung carcinoma (SCLC), a type of cancer, the tumor cells
secrete bombesin (gastrin-releasing peptide) which stimulates growth in tumor cells.
SCLC cells have high concentrations of bombesin and have a high affinity for bombesin
receptors.
Cancer as a Disease of Development:
There are many reasons to view malignant tumor (cancer) and metastasis (spreading of
cancer) in terms of development:
 Context-dependent tumor
 Cancer Stem Cell hypothesis
 Reactivation of embryonic migration in cancer – metastasis
 Epigenetic gene regulation of cancer
1. Context-Dependent Tumor (Effect of Cellular Environment):
Many tumor cells (cancer cells) have normal genomes, and whether or not these tumors
are malignant (able to spread) depends on their environment. For example,
Teratocarcinoma is a tumor of germ cells or stem cells. Teratocarcinomas are malignant
growths of cells that resemble the inner cell mass of the mammalian blastocyst (a
mammalian blastula in which some differentiation of cells has occurred), and they can

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kill the organism. However, if a teratocarcinoma cell is placed on the inner cell mass of
a mouse (mammal) blastocyst, it will become part of the blastocyst, lose its malignancy,
and divide normally. If its cellular progeny (daughter cells) become part of the germline,
sperm or egg cells formed from the tumor cell will transmit the tumor genome to the next
generation. Thus, whether the cell becomes a tumor or part of the embryo can depend
on its surrounding cells.
 Defects in Cell-Cell Communication:
In many cases, tissue interactions are required to prevent cells from dividing. Thus,
tumors can arise through defects in tissue structure, and the surroundings of a cell are
important in determining whether the cell is cancerous or not.
 Defects in Paracrine Pathways:
Tumors can occur by disturbances of paracrine signaling between cells. In some
instances, tumor cells reactivate paracrine pathways that were used during
development. Many tumors, for example, secrete the paracrine factor Sonic hedgehog
(Shh). Shh does not act on the tumor cells themselves, but it indirectly causes the
production of factors that support tumor cells. If the Shh pathway is blocked, the tumor
returns to normal (tumor is finished).
 Differentiation Therapy:
Cancer cells, in many ways, resemble embryonic cells, and they become normal if they
are made to differentiate (cancer cells are non-differentiated just like embryonic cells).
Certain leukemias (blood cancer) can be controlled by making their cells differentiate
rather than proliferate (rapid cell divisions).
2. Cancer Stem Cell Hypothesis:
The cancer stem cell hypothesis postulates that the malignant part of a tumor arises
from an adult stem cell.

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The properties of cancer cells resemble those of adult stem cells. Tumor cells may be
stem cells that have mutated such that they can exist outside their niche (fixed location
of stem cells). Most stem cells die when they leave their niche, but many tumor cells
have amplified the genes that block apoptosis (programmed cell death/cell suicide).
3. Reactivation of Embryonic Migration in Cancer – Metastasis:
Metastasis is the invasion of the malignant cells into other tissues (spreading of cancer).
Like embryonic cells, tumor cells migrate and form colonies. In cancer metastasis,
cadherin levels are downregulated (reduced), as a result, the cells become able to
spread into other tissues.
Another phase of metastasis involves the digestion of extracellular matrices by
metalloproteinases. These enzymes are used by migrating embryonic cells to digest a
path to their destination (hence proving that tumor cells migrate just like embryonic
cells).
4. Epigenetic Gene Regulation of Cancer:
Two types of genes control cell division: (1) Oncogenes (cancer/tumor genes, in normal
form they are called proto-oncogenes) promote cell division, reduce cell adhesion, and
prevent cell death. These genes promote tumor formation and metastasis. (2) Tumor
suppressor genes inhibit cell division and increase the adhesion between cells; they can
also induce apoptosis (programmed cell death/cell suicide) of rapidly dividing cells.
 Regulation of oncogenes and tumor suppressor genes:
The action of oncogenes and tumor suppressor genes has to be very finely regulated.
One might get cancer if faulty methylation (attachment of methyl group – inhibition of
gene expression) either mistakenly (by mistake) methylated the tumor suppressor

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genes (turning them off) or inappropriately demethylated (remove methyl group) the
oncogenes (turning them on).
 Effect of mutations:
Numerous mutations occur in each cancer cell. DNA has several means of protecting
itself from mutations:
Proofreading: The editing subunits on DNA polymerase (proofreading function) get rid of
mismatched bases and insert the correct ones.
DNA repair enzymes: A set of enzymes repair DNA when the DNA has been damaged by
light or by cellular compounds (i.e. products of metabolism).
In cancer cells, the genes encoding these DNA repair enzymes are inactivated by
methylation. Once DNA repair enzymes have been downregulated
(decreased/reduced), the number of mutations increases.
 Combination of genetic and epigenetic factors:
Tumors can be generated by a combination of genetic and epigenetic (gene regulation)
means. Changes in DNA methylation can activate oncogenes and repress tumor-
suppressor genes, thereby initiating tumor formation. Another possibility is that
oncogenes can cause the methylation of tumor suppressor genes, which also aids
tumorigenesis (oncogenesis). Moreover, the tissue environment of the cell may be
critical in regulating these processes. The complexities of tumors, including their
multiple somatic mutations and their resistance to substances that cause apoptotic cell
death, may best be explained by a combination of genetic and epigenetic factors and
not just by the basis of mutations.

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Figure: Cancer can arise (A) if tumor-suppressor genes are inappropriately turned off by
DNA methylation or (B) if oncogenes are inappropriately demethylated (activated).