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Reprogramming Cancer Cells in Endocrine-Related Tumors: Open Issues M. Tafani1,3, G.A. Perrone2, B. Pucci3, A. Russo4, M. Bizzarri1, JI Mechanick5, A. Carpi6 and M.A. Russo*,3 1
Department of Experimental Medicine, Sapienza University of Rome, Italy; 2UOC Pathologic Anatomy, San Filippo Neri Hospital, Rome, Italy; 3Laboratory of Cellular and Molecular Pathology, IRCCS San Raffaele Pisana, Rome, Italy; 4 Department of Surgical Pathology, IRCCS Istituto Regina Elena, Rome, Italy; 5Division of Endocrinology and Metabolism, Mount Sinai Hospital, New York, USA; 6Department of Clinical and Experimental Medicine, University of Pisa, Italy Abstract: Reprogramming technologies have been developed to revert somatic differentiated cells into pluripotent stem cells that can be differentiated into different lineages potentially useful in stem cell therapy. Reprogramming methods have been progressively refined to increase their efficiency, to obtain a cell population suitable for differentiation, and to eliminate viral plasmid which could be responsible for many unwanted side-effects when used in personalized medicine. All these methods are aimed to introduce into the cell genes or mRNAs encoding a set of four transcription factors (OCT4, SOX-2, KLF-4 and c-MYC) or a set of three lincRNAs (large intragenic non-coding RNAs) acting downstream of the reprogramming transcription factors OCT-4, SOX-2 and NANOG. Translational clinical applications in human pathologies and in developmental, repair and cancer biology have been numerous. Cancer cells can be, at least in principle, reprogrammed into a normal phenotype. This is a recently raised issue, rapidly advancing in many human tumors, especially endocrine-related cancers, such as breast, prostate and ovarian ca. The present review aims to describe basic phenomena observed in reprogramming tumor cells and solid tumors and to discuss their meaning in human hormone-related cancers. We will also discuss the fact that some of the targeted transcription factors are "normally" activated in a number of physiological processes, such as morphogenesis, hypoxia and wound healing, suggesting an in vivo role of reprogramming for development and homeostasis. Finally, we will review concerns and warnings raised for in vivo reprogramming of human tumors and for the use of induced pluripotent stem cells (iPSCs) in human therapy.
Keywords: Cellular and molecular rehabilitation, endocrine-related cancer, HIF-1alpha, hypoxia, iPSC, NFkB, OCT-4, reprogramming cancer cells, SOX-2. INTRODUCTION Regenerative Medicine is a new branch of the medical sciences that originated from the convergence of many basic and clinical research fields, including stem cell biology and pathology, maintenance and repair of post-mitotic cells, cell differentiation/de-differentiation, basic molecular mechanisms of morphogenesis and new rehabilitation strategies to recover cell and tissue functions. It must be noted that in the field of regenerative medicine, the stem cell field is much more rapidly advancing, thanks to the recent progresses in stem cells isolation from somatic differentiated adult cells [1, 2]. The landmark paper published by Takahashi and Yamanaka in 2006 [3] illustrated the induction of pluripotent stem cells from somatic normal cells, simply using a defined set of transcription factors (OCT-4, KLF-4, SOX-2 and c-MYC, indicated by the acronym OKSM). It is evident that this paper represents a breakthrough in the recent history of science, opening a completely new field in Biology and Medicine, originating a compulsive research activity in many *Address correspondence to this author at the Laboratory of Cellular and Molecular Pathology, IRCCS San Raffaele Pisana, Via di Val Cannuta, 247 - 00166 - Roma, Italy; Tel/Fax: +39-06-52253701; E-mails:
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laboratories around the world, being cited more than 5000 times in 6 years and motivating the assignment to the Author of the 2012 Nobel Prize for Physiology and Medicine after such a short time. We are only at the beginning in analyzing all the consequences of this revolutionary principle and in evaluating its implications in Biology, in Pathology, in human diseases and in regenerative medicine. At present, various laboratories are studying the reprogramming of tumor cells and its effects in cancer progression and malignancy, trying to understand two principal aspects: can reprogramming revert the transformed phenotype? Is it possible through this procedure to block or slow tumor progression inhibiting the occurrence of invasion and metastasis? Finally, specific aspects of tumor progression such as hormone-dependence and the deviations of the tumor cells from the normal differentiation program could be better understood by clarifying genetic and epigenetic mechanisms of the reprogramming. In this review we will briefly examine methodologies and some general implications of reprogramming differentiated cells and, in particular, what are the consequences in cancer stem/differentiated cells, including in those of the endocrinerelated tumors. Additionally, we will try to highlight, in perspective, the possible importance of in vivo reprogramming © 2014 Bentham Science Publishers
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as an adaptive response to pathological conditions (hypoxia and tissue damage), in developing and maintaining normal tissues and in contributing to the generation of a malignant tumor, in producing recurrences, and in facilitating progression. REPROGRAMMING TECHNOLOGY IN NORMAL CELLS The use of reprogramming technologies has been developed to revert normal somatic differentiated cells (NSDCs), such as fibroblasts, into patient-specific induced-pluripotent stem cells (iPSCs) that can be easily differentiated into different lineages, potentially useful in cell therapy and regenerative medicine. The method allows to insert into the cell, by plasmid transfection, a set of four transcription factors OKSM which have been demonstrated to be critical for stemness and cell differentiation [3]. Reprogramming methods have been progressively refined to be applicable to human cells [4], to increase their specificity and efficiency, to obtain a cell population easily suitable for differentiation [4], and to eliminate the use of viral plasmid which could be responsible for unwanted side-effects when used in personalized medicine [5]. These new methodological variations include the use of mRNAs encoding the above transcription factors [6], a set of micro-RNAs [7] or a set of three lincRNAs (large intragenic non-coding RNAs) acting downstream of the canonical reprogramming transcription factors OCT-4, SOX-2 and NANOG [8], and, more recently, the use of small molecules, such as non-steroidal anti-inflammatory drugs (NSAIDs) and 4-hydroxytamoxifen, which can functionally replace the canonical transcription factors [9, 10]. Additionally, recent advances have shown that in some cases it is possible to address the differentiation of a cell in a cognate cell by activating one or two specific transcription factors, which are responsible for intermediate steps in the reprogramming pathway [11, 12]. Mature and functional myocardiocytes have been differentiated into pacemaker cells (induced sino-atrial cells) by transfecting a single transcription factor Tbx18 in isolated myocardiocytes as well as in vivo in rats [11]. In (Table 1) various examples of direct reprogramming, obtained recently, are listed, evidencing its Table 1.
potential importance in reparative medicine. Interestingly, the already known phenomenon of transdifferentiation (such as EMT) could be another example of this shortcut pathway in the differentiation program [13]. In any case, this elegant technology is strongly contributing to resolve various scientific, clinical and ethical problems related to the stem cells [35]. First, it demonstrated, by simply turning on the activity of a discrete set of genes, the reversibility of cellular identity after the morphogenetic differentiation and it demolished the dogma of the unidirectional and irreversible stability of gene expression associated with differentiation [1]. In addition, clarifying reprogramming mechanisms to pluripotency, will reveal the pathways of lineage switching. This could simplify the in vivo differentiation from one lineage to another for clinical purposes [1, 11, 12]. Second, the publication of the landmark Yamanaka's paper has already made possible a number of potential clinical applications in different human pathologies. Somatic cells, such as fibroblasts, taken directly from the patient, can be reprogrammed to patient-specific iPSCs, overcoming all immune compatibility problems [1]. At present, diagnostic, therapeutic and pharmacological clinical applications are in progress in human hematologic, neuronal and other conditions where cell repair is necessary [5, 14, 15]. In addition, iPSCs can be obtained from patients bearing mutated genes responsible for monogenic or complex human diseases; such cells may represent a good experimental model to study a disease at personalized level [1, 15]. Third, in the past the use of embryos as a source of pluripotent stem cells has raised many ethical controversies. The possibility to use adult autologous somatic cells to obtain stem cells for any differentiated lineage, circumvented most of bioethical concerns on embryonic stem cell research and their use in humans [2, 5]. REPROGRAMMING CANCER CELLS: WHY IT COULD BE USEFUL? Differentiated Cancer Cells (DCC) or Cancer Stem Cells (CSC) can be, at least in principle, reprogrammed into iPSCs, apparently showing a normal phenotype, utilizing the same 4 factors used for adult fibroblast or other somatic cell reprogramming [16].
Transdifferentiation Induced by Specific Transcription Factors (Modified from Ref.2)
Origin Cell
Transdifferentiated Cell
Involved Transcription Factor
Fibroblast
Skeletal Muscle cells
MyoD
Transformed myeloblast
Erythroid/MK cells, eosinophils
GATA-1
-cell
Macrophages
C/EBP or C/EBP
Pancreatic exocrine cell
Islet -cell
Pdx1, Ngn3, Mafa
Muscle precursor
Brown fat cell
C/EBP
Fibroblast
Cardiomyocyte
GATA-4, Mef2c, Tbx5
Cardiomyocyte
Pacemaker or sino-atrial cell
Tbx18
T cell
NK-T cell
BCL11B ablation
Fibroblast
Neuron
Ascl1, Brn2, Myt1
Reprogramming Endocrine-related Tumors
Reprogramming of cancer cells has at least four objectives: 1- to explore the possibility to normalize in vivo the malignant phenotype, as a contributor to the present therapeutic protocols; 2- to induce iPSCs that can be differentiated into various cell types to be used for stem cell personalized therapy, such as preparing individual cancer vaccines and performing pharmacological screenings for tumor drugsensitivity; 3-to yield a larger cancer stem cell population, available for experimental manipulation, such as personalized model of disease (mutations), and exploration of biological properties to attack resistant tumors and reduce relapses in individual patients; 4 - to better understand the tumor differentiation/dedifferentiation mechanisms in relation to the recurrences and therapeutic control of a tumor, and, more in general, to the progression and hormoneindependency. Reprogramming of cancer cell has raised a number of warnings and concerns for the use in vivo and in patients. In fact, this technique is a double-edge sword: from one side the use of canonical genes (OKSM), especially c-MYC and KLF-4, can enhance the oncogenic potential of the original tumor cells; from the other side silencing mutated oncogenes can revert at least in part the malignant phenotype; but we still do not know when and how it occurs or if it can be prevented or not [19]. REPROGRAMMING SOLID HUMAN TUMORS AND CELL LINES DERIVED FROM HUMAN TUMORS Different groups have reported the reprogramming of a number of solid tumors and derived tumor cell lines, both from humans and animals. Human Gastric cancer [17], leukemia, B lymphoma, melanoma, glioblastoma [18], sarcoma [19], mammary ca [20, 21], prostate ca [22], and mouse embryonic ca have been reprogrammed with different technologies, using all or some canonical genes, originally used by Yamanaka, with/without the addition of NANOG and Lin28 [19]. In all cases the biological behavior and markers typical of embryonic stem cells were evidenced. However, reprogrammed cancer stem cells displayed important differences in inducing pluripotency and thereafter in the possibility to obtain well differentiated cell lineages. More importantly, it seems that in all cases c-myc is necessary to obtain an advanced reprogramming; considering the oncogenic potential of such gene, this imposes a big limitation on the in vivo therapeutic use of tumor iPSCs [19, 23]. Lang et al. [19] recently demonstrated that, when reprogramming sarcoma cells using the four canonical genes plus Nanog and Lin28, cancer cells lost their tumorigenicity, reduced their drug resistance, and dedifferentiated as iPSCs, apparently similar to the normal mesenchimal stem cells. These mesenchimal stem cells can, in turn, be differentiated into various lineages such as fibroblasts and hematopoietic lineages. In addition, they have shown that in their cellular model the expression of c-myc was reduced, being hypermethylated during the reprogramming process. Thus, epigenetically modifying a reprogrammed cancer cell could correct some malignant effects of oncogene activation and oncosuppressor gene inactivation, suggesting a novel strategy to control tumor progression.
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Three basic steps seem to occur during cancer stem cell reprogramming: as soon as reprogramming transcription factors are expressed, a quote of cells start to divide faster and to lose their differentiation characteristics. This is associated to the down regulation of typical somatic genes. Finally, a reduced number of cells continue to overexpress the canonical reprogramming genes, establishing a lineage with pluripotent properties, gene expression and epigenetic regulation [24]. In conclusion, the understanding of reprogramming cancer cells and their potential clinical applications are just at the beginning of a long story that could be full of good results but also could reserve disappointing surprises. REPROGRAMMING MAN TUMORS
ENDOCRINE-RELATED
HU-
Endocrine-related cancers (ERCs) typically include cancers of the breast, prostate, pituitary, testes, ovary and neuroendocrine system as well as hormone-dependent tumors derived from all other tissues, such as glioblastoma, neuroblastoma, thyroid papillary ca, and biliary system tumors. Their primary feature is the presence of a receptor for a hormone which contributes to the growth and progression of the tumor. In addition, growth and progression can be characteristically inhibited by receptor antagonists. Importantly, this allows to develop an anti-hormone therapy which helps classical oncotherapy to control tumor growth (adjuvant therapy). The loss or the absence of these receptors is considered a sign of dedifferentiation and a marker of progression. Some ERCs, such as breast, prostate, thyroid cancers, sarcoma and glioblastoma, have been reprogrammed and studied for the effects of activation of four reprogramming genes. The basic aims were a) to gain insight on the role of differentiation/dedifferentiation process in tumor progression and, in particular, on the mechanisms associated with appearance of hormone-independence; b) in addition, to obtain a negative regulation of some oncogenes or a positive expression of oncosuppressor genes that could, at least in principle, revert the transformed phenotype. In prostate ca Vencio et al. [22] have been able to reprogram CD90+ prostate cancer associated stromal cells by transfecting POU5FI, LIN28, NANOG and SOX-2. They obtained iPSC-like cells very similar to human embryonic cells showing a substantial down-regulation of malignancy associated genes, a complete inactivation of the expression of stromal genes and a normal biological behavior [22]. Normal and tumor mammary tissues have been largely tested for reprogramming to better understand development, differentiation, progression and hormone-dependency [2530]. Estrogens and progesterone play complex, either synergistic or antagonistic, roles in the mammary gland maintenance and function and in breast cancer pathogenesis. Similar contrasting roles are played by their receptors. Mammary ca can be classified as subgroups on the basis of a combination of the immunohistochemistry of 3 receptors (ER-alpha, PR and HER2a) associated to a molecular signature (gene expression). Triple negative breast ca are considered of highest malignancy and poor prognosis. All three receptors are involved in both proliferation and differentiation either in
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Table 2.
Tafani et al.
Physiological and Pathological Conditions Possibly Showing Reprogramming of Somatic Differentiated Cells and Transdifferentiation
N
Condition
Involved Gene(s)
References
1
Hypoxia (HIF adaptation)
SOX-2, OCT-4, c-MYC, KLF-4
[18, 32]
2
Tissue Repair and Maintenance
c-MYC, SOX family, OCT4
[2, 9, 14, 15]
3
EMT (HIF/NFkB adaptation)
SOX-2, OCT-4, c-myc, NANOG
[2, 13, 26]
4
Tumor Progression
c-MYC, OCT-4, KLF-4, NANOG, SOX family
[16, 17, 19, 27]
5
Morphogenesis and development
SOX-2, c-MYC, OCT-4, KLF-4
[20, 23, 24, 27, 29]
morphogenesis and during mammary ca growth and progression. Reprogramming is involved in the acquisition of resistance by inhibiting their expression [25-27]. Typically, SOX2 activation correlates with the loss of hormone and EGF dependency [27], and KLF-4 expands breast stem cells by reprogramming differentiated cells to iPSCs [28, 29]. In conclusion, now we know that hormone receptors, including ERs, can be abnormally expressed in many human tumors, and that this may constitute the basis for an hormonal anticancer therapy. Unfortunately, these tumors lose the receptors as they progress toward malignancy, probably due to differentiation reprogramming. Therefore, a better control of this process, for instance through an epigenetic reprogramming [30], could maintain the hormone-sensitivity and dependency. DOES REPROGRAMMING OF SOMATIC CELLS OCCURS IN VIVO? By examining the previous literature, it is evident that canonical genes or analogous genes used for in vitro reprogramming are expressed in a number of physiological and pathological human and experimental conditions (Table 2). It appears that they are involved every time cell stemness needs to be maintained and/or induced [2, 18]. Although there is no much information on the occurrence of reprogramming in vivo in human pathology, a number of papers suggest that it could occur as a part of cell/tissue formation and repair pathways, such as those activated during hypoxia, wound healing, epithelial-to-mesenchymal transition (EMT), tumor progression, development and morphogenesis (Fig. 1). Hypoxia has been shown to change drastically the phenotype of a transformed cell in the early phase of tumor formation by activating hypoxia inducible factor (HIF)-1 alpha and -2 alpha and through the expression of hundred of genes that exponentially increase the size of a tumor and its malignancy phenotype [31]. These hypoxia related changes include also the EMT, an increase in self-renewal capability, the appearance of drug resistance, the loss of hormone-dependence and the invasive and metastatic capability. HIF-1 alpha also overexpresses alarmin receptors that in turn activate NFkB and hundreds of proinflammatory genes contributing to the malignant phenotype [32-35]. Interestingly, hypoxia seems to promote the self-renewal capability not only of the cancer stem cells (inducing telom-
erase), but also of differentiated populations, promoting a stem-like phenotype by upregulating canonical reprogramming factors, such as OCT-4, NANOG, c-MYC, SOX-2 and KFL-4. Therefore, the proliferative potential and the tumor cell plasticity (such as EMT) are a facet of this more general mechanism. EMT is a developmental program implying a substantial chromatin plasticity and change in gene expression for cell reprogramming [2, 13]. In tumors EMT is an improper occurrence and is associated with the acquisition of a new phenotype which seems crucial for tumor invasion and metastasis [13]. Most of these changes are related to the switch-off or decreased expression of epithelial genes in contrast with a new expression or overexpression of mesenchimal genes and markers, under control of a number of transcription factors [13]. Recent papers have identified numerous miRNAs that may harmonically regulate EMT by targeting genes that control molecular and functional characteristics of epithelial or mesenchymal cells [13]. Hypoxia seems to regulate EMT via HIF-1 alpha and its target genes including transcription factors, receptors, kinases, and microRNAs. Epigenetic regulation, such as DNA methylation and histone modifications, has also been shown to play a key role in controlling EMT [13]. Tumor progression viewed as adaptation to the hypoxia in endocrine-related human tumors includes in addition the loss of hormonal receptors (hormone-resistance) associated with the overexpression of some or all canonical reprogramming genes [16]. In breast ca cell lines SOX-2 has been demonstrated to be able to induce EMT and to increase malignancy; in human triple negative (ER-/PR/HER2-) breast ca. SOX-2 and KLF-4 appear abnormally overexpressed [27, 28], suggesting that an in vivo reprogramming can occur inducing EMT and increasing stemness of breast cancer. CONCLUSIONS Reprogramming cancer cells in human tumors is a very hot field in many laboratories around the world and these protocols could become clinically accessible in the next future. At present, the early available data suggest that two main beneficial results can be realistically expected: a new understanding of the process of malignant progression and the possibility to explore new therapeutic strategies to control cancer.
Reprogramming Endocrine-related Tumors
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Fig. (1). Cell phenotype modifications occurring in vivo and in vitro, previously termed differentiation or dedifferentiation process. Mechanisms involved are essentially epigenetic and can result in differentiation during development and morphogenesis, direct differentiation in vitro (see text), numerous abnormality of in vivo differentiative programs, including metaplasia, dysplasia, in vitro differentiation, in vitro transdifferentiation, and in vitro or in vivo reprogramming [Modified from (5)].
CONFLICT OF INTEREST
CSC
=
Cancer Stem Cell
The Authors declare any conflict of interest related to this article.
HIF
=
Hypoxia inducible factor
ER
=
Estrogen receptor
ACKNOWLEDGEMENTS
PR
=
Progesterone receptor
Partially supported by ASI (Italian Space Agency) to MARusso.
HER2
=
Human epithelial growth factor receptor 2
DISCLOSURE
[1]
This review contains comments and perspective ideas already expressed by two of us (MT and MAR) in an editorial recently published in Journal of Cancer Science and Therapy [36]. ABBREVIATIONS
REFERENCES [2] [3] [4]
iPSC
=
Induced pluripotent stem cell
[5]
OKSM
=
Canonical genes (OCT-4, KLF-4, SOX-2, c-MYC) for reprogramming
[6]
NSDC
=
Normal somatic differentiated cell
EMT
=
Epithelial Mesenchimal Transdifferention (Transition)
ERC
=
Endocrine-Related Cancer
lincRNAs
=
Large intragenic non-coding RNAs
NSAIDs
=
Non-steroidal anti-inflammatory drugs
DCC
=
Differentiated Cancer Cell
[7] [8]
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Received: March 16, 2013
Revised: March 18, 2013
Accepted: March 18, 2013
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