EditorialStem Cells in Cancer Progression and Therapy

Hua Tan ,1 Weijun Su ,2 and Xing-Ding Zhang3

1School of Biomedical Informatics, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA2School of Medicine, Nankai University, Tianjin 300071, China3School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong 510080, China

Correspondence should be addressed to Hua Tan; hua.tan@uth.tmc.edu

Received 25 February 2019; Accepted 25 February 2019; Published 5 March 2019

Copyright © 2019 Hua Tan et al. This is an open access article distributed under the Creative Commons Attribution License, whichpermits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Stem cells have been widely studied in the fields of cancerbiology. Yet, many fundamental questions regarding thespecific roles of stem cell in cancer progression and therapyremain elusive, impeding the effective clinical translation ofstem cell research. On the one hand, cancer stem cells(CSCs), which represent a small population within tumors,with potential to differentiate into heterogeneous tumor cellcolonies, are suggested to be responsible for therapy resis-tance and tumor recurrence. On the other hand, stem cellscan be used to treat hematological malignancies throughbone marrow transplantation by replenishing hematopoieticstem cells (HSCs). Stem cells play different roles in particu-lar contexts.

Since first discovered in acute myeloid leukemia (AML)by CD34+/CD38- biomarkers in 1997, CSCs attracted inten-sive efforts of research. Following the first evidence of CSCsexisting in human cortical glial tumors, CSCs were identi-fied in diverse human tumor tissues, including the breast,colon, and pancreas. Basically, CSCs display distinct biophy-siological properties and responses to various treatments,compared to terminally differentiated cancer (TDC) cells.Therapeutic paradigm targeting on CSCs rather than bulktumor cells (i.e., the TDCs) proved to be more potent inshrinking tumors.

The continuing advancement of molecular and cellularbiology, especially the rapid progress in next-generationsequencing techniques and cancer genomics analysisapproaches, is making therapeutics targeting CSCs more pre-cise and effective. The single-cell sequencing technology andspatial transcriptomics become increasingly popular andpowerful in profiling individual cells with genetic and

epigenetic hierarchy. Versatile gene editing techniques suchas CRISPR/Cas9 have also been harnessed to study CSCs inhuman tumors. Collectively, the molecular signatures ofCSCs as well as CSC-initiated tumor cell lineage, such as genemutation, gene and protein expression, microRNA regula-tions, DNA methylation, and histone modification, can bediscerned and even edited in an unprecedentedly high resolu-tion, which provides a unique opportunity for designing tar-geted and immune-based therapies.

Cancer has long been considered as a genetic disease,where genetic evolution of cancer cells shapes the tumorprogression. Gene mutation is a stochastic process andhence results in unsynchronized mutation patterns in cells.Meanwhile, epigenetic markers changed dramatically overtumor evolution. Therefore, cancer cells in a tumor form adynamic ecosystem of multiple colonies with heterogeneityin molecular signatures. Some of the colonies exemplifystem-like cell properties and are suggested to sustain thegrowth and expansion of the whole system. This complexand ever-changing system can be depicted and simulatedby mathematical models. During the past years, mathemat-ical models have played a critical role in generating and test-ing hypothesis regarding cancer progression. Tumor growthunder various conditions including drug treatment has beenwell addressed by computational models. Vital biologicalprocesses, such as CSC lineage commitment, genetic evolu-tion, oncogenic signaling cascades, neovascularization, andtumor cell-microenvironment interactions, have been care-fully investigated. Systems biology approaches integratingexperimental data, bioinformatics analysis, and computa-tional model are expected to play an increasingly significant

HindawiStem Cells InternationalVolume 2019, Article ID 3507604, 2 pageshttps://doi.org/10.1155/2019/3507604

role in studying CSC-initiated and driven human cancerprogression. The challenging part is to generate adequateyet nonredundant biomedical data at various scales (spatialand temporal) for model construction, calibration, and vali-dation, towards enhancing the prediction capabilities of thein silico models.

While CSCs are deemed culprit of most therapy resis-tance and cancer relapse, stem cells derived from normaltissues can be leveraged to treat human malignancies. Viatransplantation, HSCs were used to treat leukemia by replen-ishing the diminished blood cell population. Neural stemcells and human umbilical cord blood-derived mesenchymalstem cells (MSCs) were genetically transformed to treat glio-mas. In these stem cell-based anticancer therapies, engi-neered stem cells stably express cancer suppressor genes orfunction as nanomedicine carriers to deliver cytotoxic agentstargeting cancer cells. Strikingly, stem cells are also found toplay an important role in cancer immunotherapy, by contin-uously replenishing the exhausted anticancer T-cells. Despitetechnique advancement, challenges existed. In particular, dueto incomplete interpretation of the underlying molecularmechanisms, the treatment efficacy and durability of humancancers remain suboptimal in many cases. Additionally, therisk of tumorigenic transformation of the transplanted stemcells cannot be ignored. Upon being recruited into tumormicroenvironment, stem cells might be educated into“cancer-favored” and reciprocally fuel tumor cells. Thesemultifaceted interactions between stem cells and cancer cellsshould be taken into account while considering antitumortherapy with stem cells.

In the current special issue, we have solicited researcharticles and reviews that are aimed at addressing the biolog-ical and clinical questions regarding CSC-driven tumor pro-gression and cancer treatment resistance and stem cell-basedanticancer therapy. We stress on the molecular basis of howCSCs adapt to sustain the tumor progression under bothphysiological and stiff conditions such as local hypoxia andanticancer drug delivery. We also desire work exploring bio-logical processes under stem cell transplantation therapy,such as how the stem cells home to the local environment,differentiate into progeny tumor cells, and/or exert para-crine effects.

B. Chen et al. explored the potential safety issues in theapplication of human bone marrow mesenchymal stem cells(hBM-MSCs) to regenerative medicine and tissue engineer-ing. They revealed that hBM-MSC-conditioned medium(hBM-MSC-CM) promotes gastric cancer development viaupregulation of c-Myc by both in vitro and in vivo experi-ments, which may be a potential risk factor and/or a thera-peutic target for clinical applications.

D. Liu et al. conducted an integrative genome-wide anal-ysis on gene expression and DNA copy number variations ina rare but aggressive malignancy—primary small-cell esoph-ageal carcinoma (SCEC). They carried out a de novo expres-sion array on three matched sets of primary SCEC andadjacent normal tissue samples procured from their institu-tional tissue bank. Stem cell-related pathways, WNT andNotch signaling, were shown to play significant roles inSCEC in this study.

M. Maldonado et al. studied the impact of humanWharton’s jelly-derived MSCs (hWJ-MSCs) in in vitromaturation (IVM) of cumulus oocyte complexes (COCs).They demonstrated that hWJ-MSCs’ differentiation poten-tial and the presence of coordinated paracrine interactionbetween the stem cells and COCs are two prerequisitesfor the hWJ-MSCs to improve the IVM of COCs. Underappropriate conditions, the paracrine factors produced inthe coculture system with DMEM-F12 may help developsynthetic media for desired in vitro culture of COCs. Thiswork stands for a good attempt to research the paracrineeffect imposed by stem cells on the cultured cells, especiallyusing novel WJ-derived stem cells. The strategy and con-clusions may have ramifications for cancer treatment viastem cell transplantation.

Y. Shi et al. addressed the differentiation of humanumbilical cord mesenchymal stem cells (hUC-MSCs) intoneuron-like cells. Working on human umbilical cord tis-sue, they proved that edaravone, a low-molecular antioxi-dative agent, can dose-dependently induce hUC-MSCs todifferentiate into neuron-like cells. This study provides anovel method for neural-lineage induction from MSCsand demonstrates the potential applications of MSCs inregenerative medicine.

Y. Jiao et al. investigated the mechanisms underlyinghUC-MSC-based cancer therapy. They evaluated the effectof secreted factors of hUC-MSCs on the breast cancer cellline MCF7 in terms of morphological changes, cell viability,cell cycle, apoptosis, DNA fragmentation, and interleukin-1β(IL-1β) secretion and confirmed that the secreted factors ofhUC-MSCs could cause MCF7 cell death by inducing pyrop-tosis. Their results may enable the community to betterunderstand the effect of hUC-MSCs on cell-based breast can-cer therapy, as well as its associated molecular basis.

While this special issue represents an exciting start pointto address the fundamental questions regarding stem cells incancer biology and therapy, many challenges regarding theclinical effectiveness and biosafety still remain to be con-quered, as mentioned above. We appeal more intense atten-tion and participation in this promising field in the future,especially the involvement of new concepts and technologiessuch as single-cell sequencing, spatial transcriptomics, geneediting, and immunotherapy in the stem cell-related cancerresearch. We expect a new era in which stem cells can beelaborately tuned to fight for cancers, with detrimental effectstrimmed and merits maximized.

Conflicts of Interest

The authors declare that there is no conflict of interestregarding the publication of this editorial article.

Hua TanWeijun Su

Xing-Ding Zhang

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