Cancer remains one of the leading lethal diseases worldwide. Identifying biomarkers of cancers might provide insights into the strategies for the development of novel targeted anti-cancer therapies. Leucine-rich repeat-containing G protein- coupled receptor 5 (Lgr5) has been recently discovered as a candidate marker of cancer stem cell populations. Aberrant increased expression of Lgr5 may represent one of the most common molecular alterations in some human cancers, leading to long-term potentiation of canonical Wnt/ β -catenin signaling. On the other hand, however, Lgr5-mediated suppression in canonical Wnt/ β -catenin signaling has also been reported in certain cancers, such as B cell malignancies. Until now, therapeutic approaches targeting Lgr5-associated signaling axis are not yet clinically available. Increasing evidence have indicated that endogenous Lgr5 + cell population is implicated in tumor initiation, progression, and metastasis. This review is to summarize our current knowledge about the importance of Lgr5 in cancerbiology and the underlying molecular mechanisms of Lgr5-mediated tumor-promoting/suppressive activities, as well as potentially useful preventive strategies in treating tumor. Therefore, targeted therapeutic modulation of Lgr5 + cancer cell population by targeting Wnt/ β -catenin signaling through targeted drug delivery system or targeted genome editing might be promising for potential novel anti-cancer treatments. Simultaneously, combination of therapeutics targeting both Lgr5 + and Lgr5 − cancer cells may deserve further consideration considering the plasticity of cancer cells. Also, a more specific targeting of cancer cells using double biomarkers may be much safer and more effective for anti-cancer therapy.
Teratomas, the most common form of TGCT affecting young men and boys, were among the earliest documented tumors. The capacity to produce all three germ layers places testicular teratomas at the crux of stem cell and cancerbiology, and the study of these unusual tumors may hold clues about how natural populations of stem cells are regulated and how their differentiation is controlled. 129 mice have historically been and continue to be the most researched animal model of germ line teratomas. Early research with these teratomas paved the way for the development of ES cell technology. A variety of modifiers of teratoma incidence have been identified, the most widely studied, and one of the most potent of which is a mutation in the Dnd1 gene. This RNA binding protein post-transcriptionally regulates multiple target RNAs by antagonizing miRNA mediated repression and possibly through RNA editing or other mechanisms. Perhaps the most critical question is how misregulation of DND1 targets leads specifically to teratoma development rather than to more uniform neoplasms resulting from unbridled proliferation. Although other forms of TGCTs arise at later stages, presumably also resulting from misregulation of the cell cycle, development of teratomas seems to be limited to stages of male germ cell devel- opment surrounding the initiation of mitotic arrest in fetal life. This implies that totipotent pathways of embryonic differentiation are still available to male germ cells prior to the reprogramming events that occur during mitotic arrest. Exactly what those reprogramming events entail, and how they are mechanistically achieved, may reveal the links between regulation of the cell cycle, differentiation and neoplastic transformation.
In this review, we have summarized regulatory networks known to be behind the HMGB1-induced autophagy. HMGB1-induced autophagy plays an important role in cancerbiology, such as proliferation, migration and che- moresistance. Further investigation of novel molecular mechanisms involved in this is needed because there is clearly great potential to exploit HMGB1-induced autophagy in efforts to combat cancer from different perspectives, especially in terms of its drug resistance. A better under- standing of HMGB1-induced autophagy should provide additional insight into ways of reversing drug resistance in cancer therapy.
mathematical models (algorithms). Machines can also cor- rect algorithm mistakes by training. Machine learning algorithms are just useful components of computer-aided diagnosis and decision support system in oncology. Imaging representation and interpretation of tumor biol- ogy will require computational models to understand and predict the complex nonlinear dynamics that result in combinations of imaging features [156–158]. 3D printing is also an emerging computer-based technique that may be useful in oncology for research, surgical planning (using an exact 3D model of the patient’s organs to prac- tice a procedure), device designing and manufacturing, and tissue or organ replacement . The analysis of multi-dimensional imaging datasets is also increasingly required for imaging tumor phenotype. The correlation between imaging features obtained with different tech- niques must be explored for understanding the underlying tumor biology (Fig. 21). Significant differences in vascular, physiological, and metabolic characteristics have been identified in metastatic and nonmetastatic cancers. In this setting, high glycolytic activity and poor perfusion (vascu- lar-metabolic mismatch) result in an aggressive tumor phenotype . Finally, advances in the understanding of cancerbiology together with developments in diagnostic technologies, and expansion of therapeutic options have all contributed to the concept of personalized cancer care with accurate and specific targeting of cancer cells. Thera- nostics is the systematic integration of targeted diagnostics and therapeutics. Imaging may select the therapeutic choice and may monitor subsequent changes in the bio- logical characteristics of the tumor [161, 162].
Cancer is a disease that begins when a single cell escapes from the regulation of its own division. Cell division is the process a cell undergoes in order to make copies of itself. This division is normally regulated so that a cell divides only when more cells are required, and when conditions are favorable for division. A cancerous cell is a rebellious cell that divides without instructions from the body.
The extracellular matrix (ECM) plays an important role in cancer progression. It can be divided into the basement membrane (BM) that supports epithelial/endothelial cell behavior and the interstitial matrix (IM) that supports the underlying stromal compartment. The major components of the ECM are the collagens. While breaching of the BM and turnover of e.g. type IV collagen, is a well described part of tumorigenesis, less is known regarding the impact on tumorigenesis from the collagens residing in the stroma. Here we give an introduction and overview to the link between tumorigenesis and stromal collagens, with focus on the fibrillar collagens type I, II, III, V, XI, XXIV and XXVII as well as type VI collagen. Moreover, we discuss the impact of the cells responsible for this altered stromal collagen remodeling, the cancer associated fibroblasts (CAFs), and how these cells are key players in orchestrating the tumor microenvironment composition and tissue microarchitecture, hence also driving tumorigenesis and affecting response to treatment. Lastly, we discuss how specific collagen-derived biomarkers reflecting the turnover of stromal collagens and CAF activity may be used as tools to non-invasively interrogate stromal reactivity in the tumor microenvironment and predict response to treatment.
Finally, when active management to restore a damaged ecosystem fails, ecologists turn to physically managing the destructive element. For instance, controlled burning eliminates accumulated biogas to prevent mine explosions. Following a large-scale oil spill, a combination of mechanical, chemical, and biological methods are used to minimize ecosystem damage of the toxic oil on native fauna and flora. Similarly, in advanced cancer patients, individualized antibody therapy using therapeutics already in use such as anti-inflammatory agents for arthritis, psoriasis, and asthma, could be used to specifically neutralize a patient’s specific cytokine “cancer swamp gas” to reduce cytokine-mediated syndromes (i.e. cachexia, bone pain, and thrombosis).
protecting DNA integrity from exogenous and/or endogenous stimuli (73,74). Sev- eral components of these pathways seem to be entrained by circadian oscillations. Nucleotide excision repair is a DNA re- pair mechanism that prevents genomes from damage caused by several sources, such as ultraviolet light irradiation and chemical mutagens (75). Nucleotide exci- sion repair in the mouse brain seems to exhibit circadian periodicity, mainly medi- ated by xeroderma pigmentosum A, a DNA damage recognition protein (76,77). Tip60, a histone acetylase of chromatin, with DNA damage response and repair competency (78), is overexpressed in cis- platin-resistant cells and its silencing sen- sitizes cells to this cancer chemotherapeu- tic agent (79). In the same study, the expression of Tip60 is regulated by the cir- cadian transcription factor Clock, provid- ing evidence that DNA repair through hi- stone acetylation is under circadian regulation. The high mobility group box 1 (Hmgb1) protein is involved in DNA mis- match repair (80) and shows a circadian rhythmic expression in rat retina (81). Apurinic/ apyrimidinic endonuclease (APE) is an enzyme component of DNA base excision repair (82). The APE/Ref-1 gene is highly expressed in SCN, the main circadian pacemaker in mammals (83). However APE/Ref-1 mRNA levels do not show circadian patterns of expression (83).
models together with studies in human cancers strongly suggest that EZH2 is involved in the development and progression of several human malignancies. EZH2 activity is up-regulated in cancer due to gain-of- function mutations, down-regulation of its suppressors, amplification of gene expression or increase of protein abundance by oncogenic pathways such as PI3K-AKT and MEK-ERK, post-transcriptional and post-translational modifications. EZH2 mediates its functions as part of PRC2 but also as an independent chromatin modulator. EZH2 downregulates the expression of tumor suppressor genes such as GSK-3β, RAD51 and P53 and upregulates oncogenes such as STAT3 and NOTCH1, promoting cancer cell survival and proliferation, increasing genomic instability and inhibiting cell differentiation. EZH2 has been particularly associated with the expansion of cancer stem cells, cell cycle progression, accumulation of DNA damage through inhibition of DNA damage repair and epithelial to mesenchymal transition. Targeted compounds inhibiting EZH2 have been introduced in cancer therapeutics with promising results in pre- clinical studies as monotherapies or in combination with traditional chemotherapy and are currently under evaluation in phase 1 and 2 clinical trials. EZH2 is critical for survival, proliferation and efficacy of effector CD4+ and CD8+ T cells but also promotes recruitment of Treg cells in sites of inflammation. Inhibition of EZH2 and DNA methyltransferase 1 (DNMT1) resulted in increased expression of the Th1-type chemokines in cancer cells, leading to increased trafficking of effector T cells to the tumor site and decreased tumor volume. As EZH2 inhibitors are currently being tested in several clinical trials as anti-cancer drugs, novel important observations are anticipated to emerge about how these compounds also affect anti-tumor immune function. In the era of cancer immunotherapy, therapeutic targeting EZH2 will pose new challenges.
14. Ogilvie GK, Fettman MJ, Mallinckrodt CH, Walton JA, Hansen RA, Davenport DJ, Gross KL, Richardson KL, Rogers Q, Hand MS: Effect of fish oil, arginine, and doxorubicin chemotherapy on remis- sion and survival time for dogs with lymphoma: A double- blind, randomised placebo-controlled study. Cancer 2000, 88:1916-1928
While therapeutic options for patients with advanced prostate cancer (PC) have improved over the last decade, castration-resistant PC (CRPC) remains a lethal disease . Recently, relevant studies have identified genomic defects in DNA repair in advanced and primary PC. This has led to clinical studies that provide a strong rationale for developing PARP inhibitors and DNA-damaging agents in this molecularly defined PC subgroup. Following the successful development of targeted agents for molecularly defined subpopulations in other cancer types [2,3], there may be an opportunity to potentially improve patient care in PC via personalized therapeutic strategies. In this article, we review the biology and clinical implications of deleterious inherited or acquired DNA repair pathway aberrations in PC.
Professor Rakesh Kumar from the George Washington University started his plenary lecture by elaborating on the significance of extra- and intra-cellular milieu in modifying the genome through chromatin remodeling and specifically discussed the value of targeting the MTA1 master chromatin remodeler, one of the most frequently up-regulated oncogenes in human cancer . MTA1 up-regulation correlates with an aggressive and invasive tumor phenotypes and unfavorable outcome for cancer patients. At the cellular level, MTA1- containing chromatin remodeling complexes regulate a range of processes including, cell survival, invasiveness, transformation, DNA-damage response, angiogenesis, metastasis and therapeutic sensitivity of tumor cells. Dr. Kumar also discussed the role of MTA1-containing chromatin remodeling complexes as a hub to modify the expression of genes with functions in embryonic stem- cell differentiation, reprogramming of pluripotent stem cells and mesenchymal as well as cancer stem cells. Furthermore, Dr. Kumar shared recent literature about the contribution of MTA1 in modifying the chemo-sensitivity of cancer cells in experimental model systems. Dr. Kumar also presented a brief summary of advances in the past two decades since the discovery of MTA1 and shared his view about the yet to be realized progress in the area of MTA1 in cancerbiology and treatment. He concluded his presentation by highlighting the roles of signal- dependent combinatorial post-translational modifications of MTA1 in determining the nature of resulting MTA1- contaning chromatin remodeling complexes and selection of downstream target genes . Finally, he discussed how selective recognition or targeting of such post-translational modifications of MTA1 could serve as superior biomarkers and targets in cancer.
Returning to Driesch and Roux, we now know that, regarding the first and second cleavages, on the one hand, vertebrate development is regulated and that, on the other, in some invertebrate species development is mosaic, but any given organism expresses only one of these two modes. In this context, cancer research should benefit from rejoining the long and successful tradition in the exact sciences and in the biology of yore of dis- carding premises and falsifying hypotheses. And yes, cancer research in particular and biology at large should welcome the Systems Biology approach, originally out- lined by Paul Weiss and Ludwig von Bertalanffy [36,37] who envisioned the advantages of adopting an organicist approach to the understanding of the living [38,39]. A new methodological outlook where mathematicians will join biologists in having an active participation in the design, exploration and interpretation of these subjects seems now necessary and timely. Simultaneously, the merging of this complementary expertise may have the added advantage of bringing into cancerbiology a tradi- tion whereby theories “... must be genuinely testable, and therefore subject to the possibility of rejection.”
Understanding normal cell behavior has been a signifi cant goal of modern biology and of course this is extremely important in defining the neoplastic process. However, it is now widely recognized that this is not enough in itself as there are a constellation of changes in the altered and forever adapting universe of the cancer cell. Hanahan and Weinberg  summarized an immense body of work by listing the ‘hallmarks’ of cancer cells and tumors a limitless replicative potential, resistance to apop tosis, insensitivity to antigrowth signals, self sufficiency in growth signals, tissue invasion and meta stasis, and sustained angiogenesis. Building on this model and our deeper understanding of cancerbiology, Luo, Solimini and Elledge  have proposed additional charac teristics, such as: evading immune surveillance ; an elevated DNA damage/replication response caused by elevated replication rates and also DNA repair defects in tumor cells ; proteotoxic stress an increase in the amount of toxic, unfolded proteins in tumor cells and the resultant heat shock protein response ; mitotic stress/chromosomal instability ; meta bolic stress the increased use of glycolysis rather than oxidative phosphorylation as a means of producing ATP ; and oxidative stress an increase in the level of reactive oxygen species in tumor cells .
Figure 3. Microenvironment in the metastasis process. Metastasis is a complicated multistep process that requires cancer cells to escape from the primary tumor, survive in the circulation, seed at distant sites and grow. Each step involves stromal cell and paracrine interactions of the microenvironment. Aberrantly secreted chemokines and cytokines from the primary tumor circulate into the blood stream, creating a pre- metastatic niche even before tumor cell mobilization. Secreted factors functionally activate bone marrow-derived cells, which are then released into the circulation to subsequently incorporate these cells into distant organs, such as lung and liver, to create a favorable microenvironment for the cancer cell to be seeded. For the cancer cells to invade into the blood circulation, proteases are produced by bone marrow-derived cells, including macrophages and fi broblasts. Following tumor cell intravasation, a series of steps is required for the establishment of secondary tumors in the metastatic sites. Disseminated cancer cells preferentially form metastases at sites where activated bone marrow-derived cells are localized and the primary tumor has created a favorable environment at the local organ. After seeding, persistent growth of the metastatic tumor requires the establishment of a vasculature that can be possibly achieved through the production of angiogenic growth factors.
Th e animal studies discussed above for the most part demonstrate a connection between stress exposure and breast tumor incidence and growth, corroborating the ﬁ ndings of a subset of the epidemiologic literature. Th is ﬁ eld suﬀ ers from a limited number of studies, however, and needs to be expanded into research directions that would strengthen its applicability to human biology. Th e most important step forward would be to extend the use of physiological measures of stress to human studies. Although, a retrospective epidemiologic design does not allow for a measurement of stress signaling parameters at the time of stress exposure, certain prospective designs may allow for incorporation of physiological stress- measurement techniques. For example, physio logical measures can be employed in prospective studies of long- term stress (such as work strain or caregiving) where the exposure is ongoing at the time of study initiation, or to test for increased cortisol levels in the presence of a history of life events. Validated methods for stress quanti- ﬁ cation that can be applied include the measurement of morning and evening salivary or blood cortisol levels [46,84]. Th e detection of anti-Epstein–Barr virus anti- bodies in the blood has also been implicated as an indirect biological marker of stress [85,86].
The spectrum theory conceptualized the entire range of metastatic competence, analogous to a diapason, which is the entire range of an instrument. To that end, the social sciences concept of a diaspora has recently been utilized to inform biologic understanding and therapeutic paradigms of cancer metastasis . A diaspora refers to the scattering or movement of a population from its original homeland. In the case of systemic metastases, the diaspora resembles an imperial colonization in which the populations spread widely and eventually conquer the new host lands (aggressive cancer clones to multiple organs). Oligometastases resemble trading post diasporas, representing a limited number of outposts with limited growth potential (less aggressive cancer clones to few organs). (Table 1, Figure 1). Systemic versus oligometastatic diasporas may be dependent on the types of mutations present in the cancer cells (quality of the diaspora migrants), the quality of the original tumor site (factors in the homeland that cause the population to migrate), and the quality of the new hostland (factors that allow immigrants to establish and flourish) (Table 2).
CSC is a general term referring to the cancer cells capable of differentiation and self-renewal which is the role of CSCs chemotherapy resistance. We should notice that the definition of CSCs does not determine their origin and the term “Cancer Stem Cell” does not mean that cancer begins from stem cell. CSCs are more differentiated than stem cells including a more limited spectrum of the cells existing in a tissue . Some cells in a tumor may un- dergo some sort of genetic or epigenetic changes in the signaling pathway which results in phenotype similar to that of stem cells. These changes may happen in different types of cells such as stem cells, progenitors, and dif- ferentiated cells. This will be further discussed in the origin of CSCs section . In 1994, CSCs were isolated for the first time. In 1855, German pathologist stated that cancers arise from the activation of dormant , em- bryonic-like cells present in mature tissue and argued that cancer does not simply appear spontaneously. 150 years later, Lapidot and colleagues came up with the CSC hypothesis .
In many types of solid tumors, cancer cells are embedded in a dense fibrillar matrix. Cytoskeletal forces are transmitted into the ECM via cell-matrix adhesions, which can lead to ECM remodeling and propagate mechanical signals to surrounding cells (43). Stiffer substrates tend to promote increased cell traction forces and lead to a more invasive phenotype (44, 45). Relaxation of tension in the substrate in laser ablation experiments (46, 47) tends to revert cell invasiveness. Moreover, ECM networks exhibit nonlinear strain stiffening (48), suggesting potential mechanical feedback mechanisms. These phenomena have been demonstrated through a number of experimental studies. Complementarily, computational models can provide quantitative, mechanistic insights toward underlying driving factors of invasive behavior in 3D ECMs – particularly to a level of detail that may be unfeasible for experiments to achieve or parse out. Computationally intensive models can capture a high degree of local details observed in high resolution experiments of cell-ECM interactions. In a recent study, a model capturing an entire cell with dynamic protrusions inside a surrounding ECM showed that dynamic filopodia can act as rigidity sensors that facilitate durotaxis in HUVECs (Fig. 2a) (49). While stiffness sensing (and many other cell behaviors) is a phenomenon exhibited by normal and cancer cells, cancer-related parameters can be tuned in generalizable models to explore disease phenotypes. In particular, the above model showed that the number and length of filopodia can modulate invasive behavior, supporting prior studies that showed that deregulation in filopodia-related functions and pathways are implicated in cancer progression and metastasis (50). In another model that incorporates dynamic local forces and force-sensitive ECM fiber-fiber crosslinks, it is demonstrated that the coupling of mechanical forces and fiber-fiber biochemical kinetics can result in ECM densification near the cell boundary, consistent with experiments in tumor and endothelial cells (51). Furthermore, the fibrillar nature of the ECM and asymmetric contractility of elongated cells can lead to long range anisotropic strain profiles in the environment due to fiber realignment (Fig. 2b) (52-54), which can also generate spatial profiles of stiffness (48).
CD44v3 levels were found elevated in head and neck squamous cell carcinoma (HNSCC) cell lines and these higher level of CD44v3 caused a significant increase in cell migration . Transfection of the CD44v3 isoform into a non-expressing HNSCC cell line resulted in increased tumor cells migration. Treatment of anti- CD44v3 antibody in those cells resulted in a decrease in vitro proliferation and cisplatin resistance . Injection of 50 cells of CD44v3 High , aldehyde dehydrogenase-1 (ALDH1) High cell populations but not CD44v3 Low , ALDH Low cells or unsorted cells from tumor-derived human HNSCC formed tumors with high efficiency in NOD/SCID mice. HA treatment of CD44v3 High , ALDH High cells stimulated a higher amount of Oct4- Sox2-Nanog accumulation . Our lab showed that a flow sorted pancreatic cancer cell population (CFPAC1- CD44 Low cells) that expressed low levels of CD44s but with expression of multiple CD44 variant isoforms also expressed higher levels of ALDH. On the other hand, cells that expressed high levels of CD44 standard isoform have relative low level of ALDH (unpublished data). This finding suggests that CD44v expression correlated with ALDH levels. Delta Np-63 directly regu- lates CD44 expression which potentiated EGFR activation and the expression of ABCC1 multidrug transporter gene which contributed to tumor cell proliferation and chemoresistance in HNSCC . ALDH was a widely ac- cepted property of CSC suggesting that CD44v may relate to stemness properties than CD44s but further functional studies need to be done in context with different cancer stages and cancer types.