Advances in Cancer Stem Cell Biology

Cancer Stem Cells (CSCs) in Drug Resistance and their Therapeutic Implications in Cancer Treatment
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Relevant ligands are expressed in niche-related cells, including vascular endothelial cells, endosteal cells, and osteoblasts. Whereas several of these ligands are membrane-bound and act as homing receptors, some of them, such as stem cell factor SCF or stroma cell-derived factor-1 SDF-1 , can also be produced and released as soluble ligands and thus can act as chemotactic factors for SC.

Depending on the organ system, homing of stem cells is a physiologic process [ , - ].

Introduction

Likewise, normal hematopoietic stem cells are detectable in the peripheral blood and undergo homing in various organs. In most solid organs, however, stem cells do not undergo redistribution and homing, unless these cells transform to metastasizing CSC. Stem cell homing of normal hematopoietic stem cells and LSC is a multi-step process and the same holds true for the invasion-metastasis cascade of CSC [ , ].

Several different molecules are involved in the homing and invasion process, including selectins and selectin-ligands, integrins and their receptors, and other cell-cell and matrix-binding molecules [ , ]. In the normal and leukemic bone marrow, several specific molecular interactions that may contribute to stem cell homing to the niche have been identified.

One important type of molecules may be cytoadhesion receptors, including integrins, selectins, CD44, or members of the cadherin family. Most of these homing receptors, including chemokine receptors and ligands of matrix molecules such as L1 or CD44, have been detected on CSC [ , , ]. Likewise, L1 is expressed on the edges of invasive colon cancers and its metastases [ , ] and the same holds true for CD44 and CD, suggesting that these molecules play a role in tumor invasion and thus disease progression [ 99 , - ].

Cancer stem cell - Wikipedia

In epithelial tumors, CSC redistribution is facilitated by the so-called epithelial-mesenchymal transition EMT , a process that is associated with a loss of specific adhesive interactions between cancer cells and the surrounding microenvironment [ , , ]. Several different molecules, including E-cadherin and L1, have been implicated in the process of EMT in solid tumors [ - ]. In hematopoietic neoplasms, similar mechanisms may apply during disease evolution. However, so far, little is known about specific alterations in CSC niche interactions in these malignancies.

In CML, LSC have been described to exhibit an adhesion defect that may explain the LSC escape from the bone marrow niche, and subsequent extramedullary spread of progenitors, which is a pathognomonic finding in this type of leukemia [ , , ].

1. Introduction

In the clonal evolution model, to achieve a durable response, it is necessary to therapeutically eliminate all clones of tumor cells that have the ability to invade and metastasize. By Ranganathan P. Example of two- and three-compartment mathematical models. Antibodies against CD also avoided grafting of these cells into mice, and decreased tumor load in those with already established disease. Currently, there are three RNAi-based therapies in early clinical trials for cancer.

Both niches are considered to act together and thereby trigger self-renewal, proliferation, migration, and redistribution of normal and neoplastic leukemic stem cells [ , - ]. Whereas the endosteal niche is considered to regulate self-renewal and quiescence of normal and neoplastic stem cells, the vascular niche is considered to regulate self-renewal, redistribution, and the leukemic spread of these cells. The postulated vascular niche may primarily be composed of endothelial arterial cells and perivascular cells, whereas the endosteal stem cell niche is primarily represented by endosteal-lining cells and osteoblasts [ , ].

In pursuit of the elusive stem cell

Hypoxia and hypoxia-inducible factors HIF may influence the fate and self-renewal capacity of stem cells in the micro-milieu of the stem cell niche in health and disease [ 14 , , - ]. So far, little is known about the mechanisms through which hypoxia regulates self-renewal and proliferation of CSC.

These cytokines may promote tumor-associated angiogenesis. It has also been described that hypoxia maintains a more stem cell-like state of progenitor cells in the BM by regulating key signaling pathways responsible for stem cell growth and survival, such as Notch or Oct4 [ , , , ]. Another important aspect is that hypoxia can trigger the production of reactive oxygen species ROS in neoplastic stem cells, which in turn leads to DNA breaks and thereby increases mutagenesis and thus the generation of more malignant subclones [ , ].

A remarkable aspect in the biology of neoplastic stem cells is plasticity and subclone formation during disease evolution which is relevant clinically as subclone formation is often associated with progression and drug resistance. Recent data suggest that in AML and CML, subclone formation is an early and frequent event in LSC development, and the same may hold true for other neoplasms, including solid tumors [ 26 , 54 , , , , , , ]. Plasticity is best explained by genetic instability.

The excessive plasticity and subsequent formation of neoplastic subclones is somehow contradictory to the hypothesis that many at least premalignant NSC are quiescent cells.

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Subclone formation and plasticity of LSC in CML may also be associated with lineage commitment and differentiation or even a lineage switch. In rare cases, subclone formation from LSC is excessive and may result in the development of two histologically unrelated but still monoclonal neoplasms [ - ]. Finally, it has also been reported that some of the hematopoietic neoplasms produce their own clonal microenvironment [ - ]. All these observations suggest that the leukemia-associated microenvironment, including the LSC niche, is a new emerging target of therapy.

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Subclone formation of CSC during evolution of a malignancy. Each change in color is indicative of the acquisition of a relevant new molecular lesion. After a certain time, one or more malignant dominant subclones expand and develop into an overt malignancy. Neoplastic stem cells are indicated by bold circles. However, the less malignant pre-malignant neoplastic stem cells may still survive because of their quiescence and other resistance-related mechanisms and may later expand and produce a relapse.

Such late relapses may not necessarily express the same oncogenic lesions driver mutations compared to the original subclone but still are derived from the same initial stem cell clone. Today, the subclonal architecture is demonstrable by deep sequencing technologies in various malignancies.

3rd SUNRISE MEETING : new advances in cancer stem cells

Notably, targeting of CSC using drugs that can kill or permanently suppress these cells may be a pre-requisite for the development of new curative treatment approaches in cancers and leukemias [ 7 , 11 , 14 , 16 , 28 ]. However, unfortunately, in many instances, CSC and normal stem cells share the same target antigens [ 64 ].

New Advances and Challenges of Targeting Cancer Stem Cells.

As a result, CSC-targeting therapies often result in the occurrence of substantial adverse side effects such as prolonged cytopenia. In this regard, it is noteworthy that the only available curative drug-therapy in AML, which is polychemotherapy, is usually also associated with prolonged cytopenia. Therefore, current research is seeking novel markers and targets that are preferentially or even selectively expressed on CSC LSC but are not expressed or less abundantly expressed by normal stem cells [ 67 , 84 , 87 ].

With regard to CD33 and CD52, clinically established targeting concepts are available [ - ]. However, unfortunately, normal stem cells also express low but detectable amounts of these surface antigens, and the respective drugs, gemtuzumab ozogamicin GO, anti-CD33 and alemtuzumab anti-CD52 have recently been removed from the oncologic market because of their toxicity profiles which may indeed result in part from their effects on normal stem cells [ - ]. The value of these agents is currently being tested preclinically and in clinical trials [ ]. Leukemic stem cells express the cell surface target antigen CD The black open histogram represents the isotype-matched control antibody.

As visible, exposure to alemtuzumab resulted in a dose-dependent decrease in AML stem cells left panel but did not result in a decrease of normal BM stem cells right panel. During the past few years, several potent targeted drugs directed against the primary dominant oncoproteins of various tumors and leukemias have been developed. Normal and neoplastic stem cells benefit from several repair mechanisms and defense systems through which these cells can escape or survive various stress reactions, toxin-exposure, or microbial attacks, and the same mechanisms are responsible for drug resistance [ 11 , 19 - 23 , 28 , , ].

In the context of neoplastic stem cells, intrinsic forms and acquired forms of resistance have been described. In most neoplasms, multiple factors and mechanisms may act together to produce intrinsic resistance. One factor may be stem cell quiescence [ 11 , 19 - 23 , , ]. Another important factor are cytokine interactions and cell-cell interactions in the CSC niche [ 14 , 19 - 23 , 28 , 54 ].

Likewise, in advanced leukemias, LSC often express MDR-1 and probably other drug efflux transporters [ 22 , - ]. Similar drug transporters have also been identified in solid tumors and in solid tumor CSC. These mutations may occur in an early phase or even prephase of the disease. Nevertheless, as soon as these small-sized subclones acquire a sufficient number of additional hits mutations , they can expand and develop into an overt disease in which neoplastic cells and CSC exhibit acquired resistance [ 26 , 28 , 54 , , ].

The use of targeted drugs must lead to a selection of these more malignant subclones over time. Mutations leading to drug resistance may occur in a number of different genes. Likewise, mutations in various tyrosine kinases may contribute to resistance against oncoprotein-targeting drugs [ - ]. Such mutations have been detected in virtually all oncogenic kinases that play a key role in human leukemogenesis or myeloproliferation and also in most other tumor models [ ].

These types of resistance are usually associated with a poor prognosis and are often accompanied by cytogenetic evidence of clonal evolution. Most of the conventional anti-cancer agents currently used in daily practice or in clinical trials are primarily acting on rapidly dividing cells that make up the bulk of the tumor, whereas most CSC and premalignant NSC are not affected.

High-dose chemotherapy and novel targeted drugs may be able to eliminate the bulk of the neoplasm and to eradicate most CSC or LSC in a given tumor or leukemia. These debulking agents are still very useful and instrumental in anti-cancer therapy. However, relapses may develop from a few residual, drug-resistant, premalignant quiescent NSC that exhibit intrinsic stem cell resistance.

These drugs may even lead to operational cures without having the potential to eradicate the disease completely [ , ]. The question is how relevant the residual often quiescent NSC are in these patients. By contrast, in AML, the mutation rate is high and relapses are always indicative of a poor outcome and are often associated with multidrug resistance. The same holds true for most solid tumors.

Introduction

In recent years, cancer stem cells have been recognized as important component in carcinogenesis and they seem to form the basis of many (if not all) tumor. The understanding of the mechanisms underlying the development and progression of cancer has advanced in recent years, leading to the emergence of .

Even imatinib can induce long-term CMR in a smaller fraction of patients [ ]. When TKI are discontinued in these patients, some of them will relapse but may again respond to imatinib or other new TKI [ ]. In solid tumor, novel TKI have also been applied in clinical trials and some of these agents are rather promising.

However, long-term remissions are usually not induced with these agents even when combined with chemotherapy. Overall, with a few exceptions, in most advanced solid tumors, no drug-based CSC-eliminating treatment approach has been developed so far. However, there are several examples where targeted drugs as single agents may lead to long-term disease control.

Another example is renal cell carcinoma, where inhibitors of the PI3K-mTOR pathway have shown to exert major anti-tumor effects [ , ]. One possible way to overcome this type of resistance may be to apply targeted antibodies, especially antibody-toxin conjugates which often act independent of the cell cycle and thus can destroy even dormant NSC. Likewise, in several types of lymphomas, the addition of pan-B-cell-targeting antibodies has substantially improved cure rates and the overall outcome survival in these patients [ , , ]. An alternative strategy is to mobilize dormant cells into the cell cycle or out of the niche where dormancy may be propagated [ , ].

A major problem is that in advanced cancer lesions, CSC not only exhibit intrinsic natural stem cell resistance but often also acquired drug resistance in more resistant and thus more malignant subclones [ 28 , 54 , ]. One strategy to address the multiple mechanisms of resistance accumulating in advanced tumor lesion is to apply drug combinations. Another strategy is to combine conventional or targeted drugs with response modifiers or agents that mobilize tumor cells into the cell cycle. An alternative approach is to select targeted drugs that can overcome acquired drug resistance resulting from point mutations in critical target genes.

Recent data suggest that Plerixafor cannot only mobilize normal hematopoietic stem cells from the bone marrow stem cell niche but also LSC and that Plerixafor-mobilized LSC may be more sensitive against certain anti-leukemic drugs [ , ]. However, it remains unknown whether all LSC can be mobilized by Plerixafor, whether the mobilization is associated with a rebound of more rapidly growing LSC in the niche and whether addition of Plerixafor to conventional chemotherapy will indeed increase response and cure rates in patients with AML or other leukemias.