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Jusino et al. J Cancer Metastasis Treat 2018;4:43 I http://dx.doi.org/10.20517/2394-4722.2018.24 Page 3 of 20

survival . We speculate that the higher relapse rates are due to the close relationship between aneuploidy,
[16]
chromosome instability, and chemotherapy resistance [17,18] .

Intra-tumor heterogeneity origins can be explained by two theories: clonal evolution and stem cells origin.
The first theory, clonal evolution, proposes that intra-tumor heterogeneity arises in response to tumor cell
adaptation . In this model, the existence of different genetic subpopulations of cells can be due to external
[1]
pressures that drive the evolution of a tumor following the Darwinian evolutionary principles . This theory
[19]
was first described in 1976 by Peter Nowell, who described cancer progression as an evolutionary process driven
by multiple somatic mutations, giving rise to uncontrolled growth and adaptation to the environment [19,20] .
Then, Loeb proposed that this evolutionary process could be accelerated by a mutator phenotype initially
caused by a mutation in genes that control genetic stability . Many mouse models have given support
[21]
to the evidence of such mechanism in mouse models, including experiments done by Fukasawa et al. ,
[22]
who demonstrated using young mice harboring a genetic knockout of p53 frequent chromosome instability,
aneuploidy, and centrosome amplification that preceded tumorigenesis. Other altered tumor suppressors that
allow genomic instability include Brca1 and Brca2 [23,24] . Oncogenes that can cause genetic instability include
K-Ras G12D , v-Ras, H-Ras G12V and c-Myc [25-29] . More recent data by the Pellman group has shown that evolution
can also occur from single, catastrophic events [30,31] . One of such mechanisms is known as chromothripsis,
which is caused by the fragmentation and rearrangements of whole chromosomes contained in micronuclei
(defined as missegregated whole chromosomes) . Interestingly, centrosome amplification and failure of the
[31]
spindle assembly checkpoint frequently cause whole chromosome losses [26,27,32-35] , implying that they may
represent primary causes of these catastrophic events. Genetic mutations not only drive cancer initiation
and progression but can sustain cancer cell survival by modulating the metabolism that supplies the high
demand of building blocks required by cancer cells. For example, it has been reported that the transcription
factors p53, c-Myc, and HIF can induce the expression and activity of glucose transporters involved in
glycolysis and the hexose monophosphate shunt to fuel the TCA cycle . Moreover, fatty acid β-oxidation is
[36]
expressed differently in glioblastoma subtypes; this generates a different response to drug treatment and leads
to lipid mobilization to generate more energetic compounds and building block for cancer development and
progression . This adaptation to the environment does not only create an effect in the microenvironment
[37]
surroundings but also alters the response to therapy by creating cells resistant to chemotherapy.

The second theory, the cancer stem cell (CSC), states that the self-renewal capacity of a stem cell leads to intra-
tumor heterogeneity . This theory does not take in consideration aberrant genetic errors that may confer
[1]
genetic advantages to the tumor as the clonal evolution theory does. The presence of CSCs was first observed
in chronic myeloid leukemia and mouse models . Furthermore, a study done in mice that were injected
[19]
with breast cancer cells demonstrated the presence of a small subset of cells that displayed the cell surface
marker of stem cells, CD44 CD24 -/low[38] . Another tenet of the CSC theory is that tissue-specific stem cells may
+
arise from the accumulation of mutations over time that can initiate tumorigenesis (local or distant), and
then become CSC . For metastasis to occur, the cancer cells from a primary tumor need to detach, invade
[39]
the vascular or lymphatic tissue, extravasate, and then proliferate by recruiting surrounding vasculature to
grow at a distant site. CSC has been implicated in metastasis through epithelial to mesenchymal transition
(EMT), a precursor of metastasis . CSC gives origin to the generation of circulating tumor cells (CTCs),
[40]
defined as rare (1 to 10 ) cancer cells that circulate in the peripheral blood [39,41] and colonize adjacent tissues;
6
thus contributing to tumor progression. External pressures create a microenvironment that changes the
phenotypic and behavioral development of a tumor. This reasoning provides an initial explanation of drug
resistance and metastasis initiation between patients with the same type of cancer [5,39] . The external pressures
can be inflammatory responses, radiotherapy, or cytotoxic chemotherapy [19,42,43] . The microenvironment
surrounding a tumor can also influence tumor fate. In a recent example, the genetic ablation of the
E2F3 transcription factor in macrophages suppresses mammary tumor metastasis into the lungs, but not
mammary tumor growth, suggesting that proper macrophage functions and specific microenvironments
maintain specific cancer cell functions .
[44]