New promising drug targets in cancer- and metastasis-initiating cells

Abstract

The unique properties of cancer- and metastasis-initiating cells endowed with a high self-renewal and aberrant differentiation potential (including their elevated expression levels of anti-apoptotic factors, multidrug transporters, and DNA repair and detoxifying enzymes) might be associated with their resistance to current clinical cancer therapies and disease recurrence. The eradication of cancer- and metastasis-initiating cells by molecular targeting of distinct deregulated signaling elements that might contribute to their sustained growth, survival, and treatment resistance, therefore, is of immense therapeutic interest. These novel targeted approaches should improve the efficacy of current therapeutic treatments against highly aggressive, metastatic, recurrent, and lethal cancers.

FIGURE 1

Proposed model of cancer initiation, progression, and metastasis and treatment resistance mediated through cancer- and metastasis-initiating cells. This scheme shows the malignant transformation of adult stem/progenitor cells into tumorigenic cancer stem/progenitor cells, also known as ‘cancer-initiating cells’, which may be induced through genetic and/or epigenetic alterations in these immature cells and changes in their local microenvironments, including the activated stromal cells. The symmetric or asymmetric division of cancer stem cells (CSCs) into transit-amplifying (TA) also designated as intermediate cells that, in turn, may generate the bulk mass of poorly, moderately, and highly differentiated cancer cells is also illustrated. Moreover, the acquisition of a migratory phenotype by tumorigenic cancer-initiating cells, which may be induced by the sustained activation of distinct oncogenic signaling pathways during the epithelial–mesenchymal transition (EMT) program, is shown. The possible invasion of certain tumorigenic and migrating cancer-initiating cells in the activated stroma, which might lead to their dissemination through the peripheral circulation at distant tissues and organs, is also illustrated. Moreover, the possible loss of the migratory phenotype of metastasis-initiating cells via the occurrence of mesenchymal–epithelial transition (MET) at secondary tumor sites is indicated. The dormancy phenomenon of metastasis-initiating cells and their possible reactivation associated with the formation of secondary tumor formation under specific microenvironmental conditions at distant sites is also illustrated. New cancer therapies, which use molecular targeting of cancer- and metastasis-initiating cells to counteract cancer progression and metastases at distant tissues and organs, are also indicated.

FIGURE 2

Potential signaling transduction pathways involved in the aggressive behavior and multidrug resistance phenotype of cancer- and metastasis-initiating cells and new cancer therapies by molecular targeting distinct signaling elements. The mitotic effects induced through the activation of distinct intracellular signaling pathways initiated by different growth factors, cytokines and chemokines in cancer stem/progenitor cells are illustrated. In particular, the possible upregulation of the expression levels of numerous gene products involved in the sustained growth, survival, invasion, and metastasis of cancer stem/progenitor cells are indicated. Moreover, a decrease in intracellular drug accumulation mediated via the ATP-binding cassette (ABC) multidrug efflux pump and enhanced drug metabolism via aldehyde dehydrogenase (ALDH) is also shown. The potential inhibitory effect induced by diverse pharmacological agents such as a selective inhibitor of receptor tyrosine kinase (RTK) activity (gefitinib, erlotinib, or lapitinib), smoothened (SMO) co-receptor of hedgehog (cyclopamine or IPI-269609), NF-κB, PI₃K or mTOR signaling element, telomerase, ABC transporters, and ALDH (diethylaminobenzaldehyde, DEAD) in cancer cells is indicated. In addition, the inhibitory effect induced by a monoclonal antibody (mAb) directed against interleukin-4 (IL-4) ligand, CD44 receptor, RTK, sonic hedgehog ligand (SHH), Wnt ligand, stromal cell-derived factor-1 (SDF-1), or an antagonist of IL-4R and CXCR4 chemokine receptor are indicated. Abbreviations: COX-2, cylooxygenase-2, MMPs, matrix metalloproteinases, VEGF, vascular endothelial growth factor, uPA, urokinase plaminogen activator.