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Page 2 of 20 Jusino et al. J Cancer Metastasis Treat 2018;4:43 I http://dx.doi.org/10.20517/2394-4722.2018.24

that hinders cancer treatment and leads to tumor recurrence and metastasis . Therefore, despite the great
[3,4]
conceptual and technological advancements in cancer research, recurrence and metastasis remain a key
clinical challenge, making cancer the second leading cause of death in the United States. In this review, we
discuss some classical experiments that have enlightened us as to our understanding toward cell cycle and
centrosome regulation in order to understand how this modulates cancer initiation, maintenance, progression,
and causes intra-tumor heterogeneity. We also discuss other causes of intra-tumor heterogeneity, such as
the cancer stem cell theory. We also discuss the single-cell sequencing technique, as a novel technique to
understand intra-tumor heterogeneity and relevant therapeutic targets that may aid our understanding of
cancer and envision a more effective treatment.

THE CAUSES AND CONSEQUENCES OF INTRA-TUMOR HETEROGENEITY IN CANCER
Intra-tumor heterogeneity describes the existence of different genetic subpopulations of cells in a given
primary tumor . Genetic heterogeneity is studied to determine the transcriptional expression, copy
[1]
number or mutational/polymorphic status of genes within a tumor to provide an overall tumor genetic
composition and determine the best treatment option for patients , which is the basis for personalized
[5]
medicine. Genetic, epigenetic, and metabolic changes are important contributors to tumor formation and
progression . Cancer stem cells, genetic and epigenetic alterations, copy number variation (CMV), single
[5]
nucleotide variants (SNV), aneuploidy, genome duplication, and chromosome instability can initiate and
sustain cancer progression and genetic heterogeneity. Intra-tumor heterogeneity supports the theory of
clonal evolution that has been forced by selective pressures such as those exerted by chemotherapy or
radiotherapy.

It is generally accepted that all cancer types display some degree of intratumoral heterogeneity, with thyroid
and prostate cancers showing less heterogeneity, and cancers that include lung, stomach, glioblastomas
and melanomas displaying a high degree of intratumoral heterogeneity . In fact, transcriptomic and
[2]
genomic profiling of multi-spatial biopsies of glioblastomas, medulloblastomas and renal cell carcinomas
demonstrated that cells within a single tumor were rarely clonal, thus explaining single-agent therapy failure
in cancers . Genetic heterogeneity determines the fate of metastasis, with highly heterogeneous cancers such
[6]
[7]
as colon displaying highly heterogeneous metastases within the same patient . On the other hand, many
high-grade serous ovarian cancers of patients with metastases are clonal, and most metastases originate
from one clone . Breast cancers are excellent examples of the role played by genetic heterogeneity in survival
[8]
outcomes of affected patients . Breast cancers are classified using mRNA expression microarrays and/or
[1]
with several pathological markers, including the epidermal growth factor 2 (Her2), the estrogen receptor
(ER), or the progesterone receptor (PR). The classification includes Luminal A (ER PR Her2), Luminal B
+
-
+
(ER PR and Her2 or Her2), Her2 (ERPRHer2 ) and basal (which includes 76% triple-negative breast
+
+
+
-
+
-
-
+
tumors, ERPRHer2) . Luminal A breast cancer patients show the best survival of all breast cancer patients,
-
-
- [9]
followed by Luminal B, Her2 and basal [10,11] . More recent studies show that hormone receptor-negative breast
+
tumors (Her2 and basal) display more chromosome instability and centrosome amplification (defined as
+
the acquisition of three or more centrosomes that promote the formation of a bipolar mitotic spindle and
equal segregation of chromosomes following mitosis) than luminal subtypes [12,13] . Also, Her2 and triple-
+
negative basal breast cancer patients that initially respond to chemotherapy tend to relapse more readily than
luminal breast cancer patients if residual disease remains . Molecular subtypes also determine the preferred
[14]
metastatic sites of breast cancer cells, since Luminal subtypes are more likely to invade the bone, and basal
[15]
subtypes are more likely to invade into the lung . The differences in survival outcomes between luminal and
hormone receptor-negative breast cancers can be explained by the plethora of treatments available to treat
luminal patients (including tamoxifen, Cdk4/Cdk6 and aromatase inhibitors). Nevertheless, the differences
in survival can only be partly explained by differences in treatments available, since similar treatments
are available for Luminal A and Luminal B breast cancers, and yet Luminal B breast cancers have poorer