Cancer biology weinberg download pdf cell cycle

Approximate correlation of early genetic events in the development of colon carcinoma the adenoma-adenocarcinoma pathway with histopathological features. Note that clinical staging typically refers to the later observations and cannot be correlated with the genetic events.

Genetic events are indicated by vertical arrows and colour-coded as follows: Blue: loss of tumour suppressor gene TSG function, red: activation of oncogenes, green: epigenetic events.

The sequence of genetic events is not necessarily obligatory, but loss of APC is typically the first event and loss of p53 typically the last one. The biology of cancer, 1st ed. Metastatic cells are less adhesive than normal cells and are able to degrade and penetrate tissue barriers such as the extracellular matrix ECM of surrounding connective tissue and the basement membrane of blood vessels.

After gaining access to the systemic circulation they can invade normal tissue at various sites in the body forming secondary colonies.

The invasion - metastasis cascade involves:. Figure 5: Steps involved in the metastatic cascade. Tumor metastasis: molecular insights and evolving paradigms. Cell [6]. Epithelial-mesenchymal transition EMT is a key transition enabling cancer cells to become motile and invasive, and ultimately form metastases in distant tissues. Cell motility is regulated by small G proteins that are activated by cytoplasmic signalling pathways controlling the assembly of new actin cytoskeleton.

Cell invasiveness is enhanced through overexpression of various matrix metalloproteinases MMPs that degrade components of the ECM. Angiogenesis , the growth of the new blood vessels, is necessary for solid tumours to continue growing beyond a certain size.

More than a dozen different proteins and several small molecules are released by tumours as signals for angiogenesis. Two proteins most important for sustaining tumour growth are vascular endothelial growth factor VEGF and basic fibroblast growth factor bFGF. Cross talk between stromal cells within the ECM and tumour cells is also vital for carcinogenesis. The following factors are thought to contribute to malignant transformation:.

Apart from the three major types of genes frequently altered in cancer, i. Genetic analysis of solid tumours revealed the presence of a high degree of genetic abnormalities, such as aneuploidy, chromosome translocations etc. This is likely due to the lack of active p53 protein, and the ability of cancer cells to avoid cell death through apoptosis.

Other mechanisms may also play a part here, e. Chromosomal instability CIN is widespread in cancer cells from epithelial origin, but much rarer in haematopoietic tumours.

Three different alterations of genetic mechanisms often observed in cancer will be briefly explained below. Loss of heterozygosity LOH : This describes a genetic phenomenon often seen with tumour suppressor genes in cancer. Since the human karyotype is diploid, mutation of one allele of a tumour suppressor gene is not sufficient to cause cancer. In heterozygous individuals, the wildtype allele will provide for a functional phenotype. Genetic analyses of LOH helped to identify the chromosomal location of many tumour suppressor genes.

Microsatellite instability MIN : This is a phenomenon often seen in colorectal cancer cells with defective DNA mismatch repair system, e. Microsatellites are regions of repetitive DNA sequences in the genome that are prone to shortening or extension if the mismatch repair enzymes are defective.

Genetic analysis of these regions can be used to identify such defects. DNA hyper- or hypomethylation: DNA methylation of gene promoter regions on CpG cytosine-phosphate-guanine sequences is an important epigenetic control mechanism to silence specific genes. In cancer, DNA hypermethylation is often involved in the silencing of tumour suppressor genes. Conversely, DNA hypomethylation may contribute to the activation of oncogenes, although the former occurs much more commonly.

Whilst cancer as such is not inherited, there are a wide range of rare familial syndromes that predispose affected family members to cancer development. We mentioned above cancer predisposition syndromes that are based on mutations in DNA repair enzyme systems Table 4, in The importance of DNA repair systems. A by far larger number of familial cancer syndromes is based on mutations of tumour suppressor genes, of which a selection is shown in Table 2.

It is interesting to note that germ line mutations of activated oncogenes are normally not inherited. They may arise during gametogenesis, but the mutant alleles are typically dominant at the cellular level, which results in disturbance of normal embryonic development, and reduced viability of these embryos.

Fortunately, the inherited cancer predisposition syndromes listed in Tables 2 and 4 are extremely rare diseases, but they represent powerful illustrations for the importance of DNA repair and tumour suppressor genes for maintaining body homeostasis.

As an increasing number of cancer-related genes or gene mutations is characterised, the potential of DNA and RNA expression testing for cancer-related applications is being explored. Principal applications include:. Gene mutation screening in families with inherited cancer predisposition syndromes, which identifies at- risk individuals in such families and allows for decisions to be made about early disease monitoring, aggressive treatment regimens and prophylactic surgery e.

Gene expression microarray analysis can be used for classification of cancer subtypes, e. Other applications include the diagnosis of benign vs. Tumour cells may be recognised by the immune system through the expression of tumour-associated antigens, but the antigenicity varies considerably between different types of antigens. In order to avoid an attack by the immune system, tumour cells use a range of strategies, such as suppression of expression of tumour-associated antigens or of MHC class 1 molecules, or even counterattack against immune cells.

Research into immunotherapy of cancers aims to devise novel strategies to support the anti-cancer immune response; principal approaches include:. The progress in our knowledge about gene mutations frequently occurring in cancers, combined with the development of modern molecular biology methods has led to both new diagnostic tools see Principal applications of genetic testing in cancer and new treatment modalities that have shown some success in the management of selected types of cancers.

The knowledge about cancer—associated genes and their role in cellular growth signalling pathways has led to the development of a considerable number of anti-cancer drugs targeting such signalling pathways: 1 monoclonal antibodies that target the extracellular domains of growth factor receptors and 2 small-molecule inhibitors , targeting either receptor tyrosine kinases or other components of growth signalling pathways, such as Ras, b-Raf or mTOR Figure.

Two examples of such successful anti-cancer agents are the monoclonal antibody Herceptin for the treatment of a specific subtype of breast cancer, and the small-molecule inhibitor Gleevec targeting the fusion protein Bcr-abl, a mutant tyrosine kinase, involved in the development of chronic myeloic leukaemia CML.

A third group of potential drug targets are some anti-apoptotic proteins that are frequently overexpressed in cancer cells. Figure 6. Targets of novel anti-cancer drugs in cellular growth signalling pathways. The cell membrane is indicated in light grey, red diamonds represent growth factors, green shows the growth factor receptor with the intracellular tyrosine kinase domain Tk indicated by the red circle.

Dotted black arrows point to cell biological outcomes of these pathways. Groups of novel anticancer drugs and their targets are shown in red. The biology of cancer. Figure 7: A summary of the 6 hallmarks of cancer. Additional capabilities crucial to cancer phenotypes that are not shown here include defects in DNA repair mechanisms and signalling interactions of the tumour microenvironment. Hallmarks of cancer: the next generation.

Cell, [7]. Self-sufficiency in growth signals: Tumours have the capacity to proliferate without external stimuli, usually as a consequence of oncogene activation. Insensitivity to growth-inhibitory signals: Tumour cells may not respond to molecules that are inhibitory to the proliferation of normal cells. Evasion of apoptosis: Tumours may be resistant to programmed cell death, as a consequence of inactivation of p53 or overexpression of anti-apoptotic proteins. Limitless replicative potential: Tumour cells have unrestricted proliferative capacity, associated with maintenance of telomere length and function.

Sustained angiogenesis: Tumours are not able to grow without formation of a vascular supply, which is induced by various factors, the most important being vascular endothelial growth factor VEGF. Ability to invade and metastasise: Tumour metastases are the cause of the vast majority of cancer deaths and depend on processes that are intrinsic to the cell or are initiated by signals from the tissue microenvironment. Log in. Clinical oncology for students. Clinical oncology for students Ideal oncology curriculum.

Clinical oncology for students Preface Epidemiology and social impact of cancer Screening and prevention Cancer biology: Molecular and genetic basis Cancer biology: Familial cancers and genetic testing Cancer diagnosis: Histopathology, cytology and tumour markers Cancer diagnosis: Staging and imaging Principles of cancer management Principles of cancer surgery Principles of radiotherapy Principles of medical therapy Principles of cancer immunotherapy Principles of palliative care Cancer survivorship Doctor patient communication and psychosocial care Ethics and professional development Breast cancer Colorectal cancer Oesophageal cancer Pancreatic cancer Lung cancer Urogenital cancers Haematopoietic and lymphoid malignancies Gynaecological cancers Soft tissue sarcomas Bone tumours Melanoma and skin cancer Central nervous system tumours Head and neck cancer Cancer of unknown primary Oncological emergencies Authors and contributors.

Jump to: navigation , search. Principles of medical biochemistry. Overexpression Overexpression Amplification Overexpression. Overexpression Amplification Overexpression Point Mutation. Burkitt lymphoma Neuroblastoma, small cell carcinoma of lung SCC of the lung. Cell-Cycle Regulators Cyclins Cyclin-dependent kinase.

Translocation Amplification Overexpression Amplification or Point mutation. These two populations evidently function symbiotically: the hypoxic cancer cells depend on glucose for fuel and secrete lactate as waste, which is imported and preferentially used as fuel by their better-oxygenated brethren.

Altered energy metabolism is proving to be as widespread in cancer cells as many of the other cancer-associated traits that have been accepted as hallmarks of cancer. This realization raises the question of whether deregulating cellular energy metabolism is therefore a core hallmark capability of cancer cells that is as fundamental as the six well-established core hallmarks.

In fact, the redirection of energy metabolism is largely orchestrated by proteins that are involved in one way or another in programming the core hallmarks of cancer. When viewed in this way, aerobic glycolysis is simply another phenotype that is programmed by proliferation-inducing oncogenes. Currently, therefore, the designation of reprogrammed energy metabolism as an emerging hallmark seems most appropriate, to highlight both its evident importance as well as the unresolved issues surrounding its functional independence from the core hallmarks.

An Emerging Hallmark: Evading Immune Destruction A second, still-unresolved issue surrounding tumor formation involves the role that the immune system plays in resisting or eradicating formation and progression of incipient neoplasias, late-stage tumors, and micrometastases.

The long-standing theory of immune surveillance proposes that cells and tissues are constantly monitored by an ever-alert immune system, and that such immune surveillance is responsible for recognizing and eliminating the vast majority of incipient cancer cells and thus nascent tumors.

According to this logic, solid tumors that do appear have somehow managed to avoid detection by the various arms of the immune system or have been able to limit the extent of immunological killing, thereby evading eradication.

The role of defective immunological monitoring of tumors would seem to be validated by the striking increases of certain cancers in immunocompromised individuals Vajdic and van Leeuwen, However, the great majority of these are virus-induced cancers, suggesting that much of the control of this class of cancers normally depends on reducing viral burden in infected individuals, in part through eliminating virus-infected cells.

The results indicated that, at least in certain experimental models, both the innate and adaptive cellular arms of the immune system are able to contribute significantly to immune surveillance and thus tumor eradication Teng et al.

Unanswered in these particular experiments is the question of whether the chemical carcinogens used to induce such tumors are prone to generate cancer cells that are especially immunogenic. Clinical epidemiology also increasingly supports the existence of antitumoral immune responses in some forms of human cancer Bindea et al. Additionally, some immunosuppressed organ transplant recipients have been observed to develop donorderived cancers, suggesting that in the ostensibly tumor-free donors, the cancer cells were held in check, in a dormant state, by a fully functional immune system Strauss and Thomas, This might be taken as an argument against the importance of immune surveillance as an effective barrier to tumorigenesis and tumor progression.

In truth, the above discussions of cancer immunology simplify tumor-host immunological interactions, as highly immunogenic cancer cells may well evade immune destruction by disabling components of the immune system that have been dispatched to eliminate them.

Both can suppress the actions of cytotoxic lymphocytes Mougiakakos et al. This depiction contrasts starkly with the earlier, reductionist view of a tumor as nothing more than a collection of relatively homogeneous cancer cells, whose entire biology could be understood by elucidating the cellautonomous properties of these cells. We enumerate here a set of cell types known to contribute in important ways to the biology of many tumors and discuss the regulatory signaling that controls their individual and collective functions.

Most of these observations stem from the study of carcinomas, in which the neoplastic epithelial cells constitute a compartment the parenchyma that is clearly distinct from the mesenchymal cells forming the tumor-associated stroma.

The Cells of the Tumor Microenvironment Upper An assemblage of distinct cell types constitutes most solid tumors. Both the parenchyma and stroma of tumors contain distinct cell types and subtypes that collectively enable tumor growth and progression.

Lower The distinctive microenvironments of tumors. The multiple stromal cell types create a succession of tumor microenvironments that change as tumors invade normal tissue and thereafter seed and colonize distant tissues. The abundance, histologic organization, and phenotypic characteristics of the stromal cell types, as well as of the extracellular matrix hatched background , evolve during progression, thereby enabling primary, invasive, and then metastatic growth.

The surrounding normal cells of the primary and metastatic sites, shown only schematically, likely also affect the character of the various neoplastic microenvironments. Not shown are the premalignant stages in tumorigenesis, which also have distinctive microenvironments that are created by the abundance and characteristics of the assembled cells. In recent years, however, evidence has accumulated pointing to the existence of a new dimension of intratumor heterogeneity and a hitherto-unappreciated subclass of neoplastic cells within tumors, termed cancer stem cells CSCs.

Although the evidence is still fragmentary, CSCs may prove to be a common constituent of many if not most tumors, albeit being present with widely varying abundance. CSCs were initially implicated in the pathogenesis of hematopoietic malignancies Reya et al.

In some tumors, normal tissue stem cells may serve as the cells-of-origin that undergo oncogenic transformation to yield CSCs; in others, partially differentiated transit-amplifying cells, also termed progenitor cells, may suffer the initial oncogenic transformation thereafter assuming more stem-like character.

Once primary tumors have formed, the CSCs, like their normal counterparts, may self-renew as well as spawn more differentiated derivatives; in the case of neoplastic CSCs, these descendant cells form the great bulk of many tumors.

It remains to be established whether multiple distinct classes of increasingly neoplastic stem cells form during inception and subsequent multistep progression of tumors, ultimately yielding the CSCs that have been described in fully developed cancers. This concordance suggests that the EMT program not only may enable cancer cells to physically disseminate from primary tumors but also can confer on such cells the self-renewal capability that is crucial to their subsequent clonal expansion at sites of dissemination Brabletz et al.

Nevertheless, the importance of CSCs as a distinct phenotypic subclass of neoplastic cells remains a matter of debate, as does their oftcited rarity within tumors Boiko et al. Indeed, it is plausible that the phenotypic plasticity operating within tumors may produce bidirectional interconversion between CSCs and non-CSCs, resulting in dynamic variation in the relative abundance of CSCs.

Analogous plasticity is already implicated in the EMT program, which can be engaged reversibly Thiery and Sleeman, These complexities notwithstanding, it is evident that this new dimension of tumor heterogeneity holds important implications for successful cancer therapies.

Increasing evidence in a variety of tumor types suggests that cells with properties of CSCs are more resistant to various commonly used chemotherapeutic treatments Singh and Settleman, ; Creighton et al. Their persistence may help to explain the almost-inevitable disease recurrence following apparently successful debulking of human solid tumors by radiation and various forms of chemotherapy.

Hence, CSCs may represent a double-threat, in that they are more resistant to therapeutic killing and, at the same time, endowed with the ability to regenerate a tumor once therapy has been halted.

This phenotypic plasticity implicit in CSC state may also enable the formation of functionally distinct subpopulations within a tumor that support overall tumor growth in various ways. Observations like these indicate that certain tumors may acquire stromal support by inducing some of their own cancer cells to undergo various types of metamorphosis to produce stromal cell types rather than relying on recruited host cells to provide their functions.

The discovery of CSCs and biological plasticity in tumors indicates that a single, genetically homogeneous population of cells within a tumor may nevertheless be phenotypically heterogeneous due to the presence of cells in distinct states of differentiation.

However, an equally important source of phenotypic variability may derive from the genetic heterogeneity within a tumor that accumulates as cancer progression proceeds. Such thinking is increasingly supported by in-depth sequence analysis of tumor cell genomes, which has become practical due to recent major advances in DNA and RNA sequencing technology.

Thus the sequencing of the genomes of cancer cells microdissected from different sectors of the same tumor Yachida et al. Endothelial Cells Much of the cellular heterogeneity within tumors is found in their stromal compartments.

Prominent among the stromal constituents are the cells forming the tumor-associated vasculature. Mechanisms of development, differentiation, and homeostasis of endothelial cells composing the arteries, veins, and capillaries were already well understood in Over the last decade, a network of interconnected signaling pathways involving ligands of signal-transducing receptors displayed by endothelial cells e. These newly characterized pathways have been functionally implicated in developmental and tumor-associated angiogenesis and illustrate the complex regulation of endothelial cell phenotypes Pasquale, ; Ahmed and Bicknell, ; Dejana et al.

Such knowledge may lead, in turn, to opportunities to develop novel therapies that exploit these differences in order to selectively target tumor-associated endothelial cells. Closely related to the endothelial cells of the general circulation are those forming lymphatic vessels Tammela and Alitalo, These associated lymphatics likely serve as channels for the seeding of metastases in the draining lymph nodes that are commonly observed in a number of cancer types.

In normal tissues, pericytes are known to provide paracrine support signals to the normally quiescent endothelium. For example, Ang-1 secreted by pericytes conveys antiproliferative stabilizing signals that are received by the Tie2 receptors expressed on the surface of endothelial cells; some pericytes also produce low levels of VEGF that serve a trophic function in endothelial homeostasis Gaengel et al.

Genetic and pharmacological perturbation of the recruitment and association of pericytes has demonstrated the functional importance of these cells in supporting the tumor endothelium Pietras and Ostman, ; Gaengel et al.

For example, pharmacological inhibition of signaling through the PDGF receptor expressed by tumor pericytes and bone marrow-derived pericyte progenitors results in reduced pericyte coverage of tumor vessels, which in turn destabilizes vascular integrity and function Pietras and Ostman, ; Raza et al. An intriguing hypothesis, still to be fully substantiated, is that tumors with poor pericyte coverage of their vasculature may be more prone to permit cancer cell intravasation into the circulatory system, enabling subsequent hematogenous dissemination Raza et al.

Although the presence of tumor-antagonizing CTLs and NK cells is not surprising, the prevalence of immune cells that functionally enhance hallmark capabilities was largely unanticipated. Over the past decade, the manipulation of genes involved in the determination or effector functions of various immune cell types, together with pharmacological inhibitors of such cells or their functions, has shown them to play diverse and critical roles in fostering tumorigenesis.

Importantly, these progenitors, like their more differentiated derivatives, have demonstrable tumor-promoting activity. On the other, the innate immune system is involved in wound healing and clearing dead cells and cellular debris. The latter subtypes of immune cells are one of the major sources of the angiogenic, epithelial, and stromal growth factors and matrix-remodeling enzymes that are needed for wound healing, and it is these cells that are recruited and subverted to support neoplastic progression.

Similarly, subclasses of B and T lymphocytes may facilitate the recruitment, activation, and persistence of such wound-healing and tumor-promoting macrophages and neutrophils DeNardo et al. Of course, other subclasses of B and T lymphocytes and innate immune cell types can mount demonstrable tumor-killing responses.

Cancer-Associated Fibroblasts Fibroblasts are found in various proportions across the spectrum of carcinomas, constituting in many cases the preponderant cell population of the tumor stroma. They are rare in most healthy epithelial tissues, although certain tissues, such as the liver and pancreas, contain appreciable numbers of a-SMA-expressing cells.

Stem and Progenitor Cells of the Tumor Stroma The various stromal cell types that constitute the tumor microenvironment may be recruited from adjacent normal tissue—the most obvious reservoir of such cell types. However, in recent years, the bone marrow has increasingly been implicated as a key source of tumor-associated stromal cells Bergfeld and DeClerck, ; Fang and Salven, ; Giaccia and Schipani, ; Patenaude et al.

Mesenchymal stem and progenitor cells have been found to transit into tumors from the marrow, where they may differentiate into the various well-characterized stromal cell types. Some of these recent arrivals may also persist in an undifferentiated or partially differentiated state, exhibiting functions that their more differentiated progeny lack. Heterotypic Signaling Orchestrates the Cells of the Tumor Microenvironment Depictions of the intracellular circuitry governing cancer cell biology e.

We provide instead a hint of such interactions in Figure 5, upper. These few well-established examples are intended to exemplify a signaling network of remarkable complexity that is of critical importance to tumor pathogenesis. Another dimension of complexity is not represented in this simple schematic: both neoplastic cells and the stromal cells around them change progressively during the multistep transformation of normal tissues into high-grade malignancies.

Such stepwise progression is likely to depend on back-andforth reciprocal interactions between the neoplastic cells and the supporting stromal cells, as depicted in Figure 5, lower. Signaling Interactions in the Tumor Microenvironment during Malignant Progression Upper The assembly and collective contributions of the assorted cell types constituting the tumor microenvironment are orchestrated and maintained by reciprocal heterotypic signaling interactions, of which only a few are illustrated.

Lower The intracellular signaling depicted in the upper panel within the tumor microenvironment is not static but instead changes during tumor progression as a result of reciprocal signaling interactions between cancer cells of the parenchyma and stromal cells that convey the increasingly aggressive phenotypes that underlie growth, invasion, and metastatic dissemination.

Cancer stem cells may be variably involved in some or all of the different stages of primary tumorigenesis and metastasis. The cancer cells, which may further evolve genetically, again feed signals back to the stroma, continuing the reprogramming of normal stromal cells to serve the budding neoplasm; ultimately signals originating in the tumor stroma enable cancer cells to invade normal adjacent tissues and disseminate.

The circulating cancer cells that are released from primary tumors leave a microenvironment created by the supportive stroma of such tumors. However, upon landing in a distant organ, these cancer cells encounter a naive, fully normal, tissue microenvironment. Consequently, many of the heterotypic signals that shaped their phenotype while they resided within primary tumors may be absent in sites of dissemination, constituting a barrier to growth of the seeded cancer cells.

Implicit in this term is the notion that cancer cells seeded in such sites may not need to begin by inducing a supportive stroma because it already preexists, at least in part.

Such permissivity may be intrinsic to the tissue site Talmadge and Fidler, or preinduced by circulating factors released by the primary tumor Peinado et al. The likelihood that signaling interactions between cancer cells and their supporting stroma evolve during the course of multistage tumor development clearly complicates the goal of fully elucidating the mechanisms of cancer pathogenesis.

For example, this reality poses challenges to systems biologists seeking to chart the crucial regulatory networks than orchestrate malignant progression. Moreover, it seems likely that understanding these dynamic variations will become crucial to the development of novel therapies designed to successfully target both primary and metastatic tumors. We do not attempt here to enumerate the myriad therapies that are under development or have been introduced of late into the clinic.

Instead, we consider how the description of hallmark principles is beginning to inform therapeutic development at present and may increasingly do so in the future.

The rapidly growing armamentarium of targeted therapeutics can be categorized according to their respective effects on one or more hallmark capabilities, as illustrated in the examples presented in Figure 6.

In fact, resulting clinical responses have generally been transitory, being followed by almost-inevitable relapses. One interpretation of this history, supported by growing experimental evidence, is that each of the core hallmark capabilities is regulated by partially redundant signaling pathways.

Consequently, a targeted therapeutic agent inhibiting one key pathway in a tumor may not completely shut off a hallmark capability, allowing some cancer cells to survive with residual function until they or their progeny eventually adapt to the selective pressure imposed by the therapy being applied.

Such adaptation, which can be accomplished by mutation, epigenetic reprogramming, or remodeling of the stromal microenvironment, can reestablish the functional capability, permitting renewed tumor growth and clinical relapse. Given that the number of parallel signaling pathways supporting a given hallmark must be limited, it may become possible to target all of these supporting pathways therapeutically, thereby preventing the development of adaptive resistance.

In response to therapy, cancer cells may also reduce their dependence on a particular hallmark capability, becoming more dependent on another; this represents a quite different form of acquired drug resistance. Some have anticipated that effective inhibition of angiogenesis would render tumors dormant and might even lead to their dissolution Folkman and Kalluri, Instead, the clinical responses to antiangiogenic therapies have been found to be transitory Azam et al.

In certain preclinical models, where potent angiogenesis inhibitors succeed in suppressing this hallmark capability, tumors adapt and shift from a dependence upon continuing angiogenesis to heightening the activity of another instead—invasiveness and metastasis Azam et al. By invading nearby tissues, initially hypoxic cancer cells evidently gain access to normal, preexisting tissue vasculature.

The applicability of this lesson to other human cancers has yet to be established. Therapeutic Targeting of the Hallmarks of Cancer Drugs that interfere with each of the acquired capabilities necessary for tumor growth and progression have been developed and are in clinical trials or in some cases approved for clinical use in treating certain forms of human cancer.

Additionally, the investigational drugs are being developed to target each of the enabling characteristics and emerging hallmarks depicted in Figure 3, which also hold promise as cancer therapeutics. The drugs listed are but illustrative examples; there is a deep pipeline of candidate drugs with different molecular targets and modes of action in development for most of these hallmarks.

For example, the deployment of apoptosis-inducing drugs may induce cancer cells to hyperactivate mitogenic signaling, enabling them to compensate for the initial attrition triggered by such treatments. Thus, in particular, we can envisage that selective cotargeting of multiple core and emerging hallmark capabilities and enabling characteristics Figure 6 in mechanism-guided combinations will result in more effective and durable therapies for human cancer.

The six acquired capabilities—the hallmarks of cancer—have stood the test of time as being integral components of most forms of cancer. Similarly, the role of aerobic glycolysis in malignant growth will be elucidated, including a resolution of whether this metabolic reprogramming is a discrete capability separable from the core hallmark of chronically sustained proliferation.

We remain perplexed as to whether immune surveillance is a barrier that virtually all tumors must circumvent, or only an idiosyncrasy of an especially immunogenic subset of them; this issue too will be resolved in one way or another.

It is unclear at present whether an elucidation of these epigenetic mechanisms will materially change our overall understanding of the means by which hallmark capabilities are acquired or simply add additional detail to the regulatory circuitry that is already known to govern them.

Similarly, the discovery of hundreds of distinct regulatory microRNAs has already led to profound changes in our understanding of the genetic control mechanisms that operate in health and disease. By now dozens of microRNAs have been implicated in various tumor phenotypes Garzon et al. Here again, we are unclear as to whether future progress will cause fundamental shifts in our understanding of the pathogenetic mechanisms of cancer or only add detail to the elaborate regulatory circuits that have already been mapped out.

Finally, the circuit diagrams of heterotypic interactions between the multiple distinct cell types that assemble and collaborate to produce different forms and progressively malignant stages of cancer are currently rudimentary.

In another decade, we anticipate that the signaling circuitry describing the intercommunication between these various cells within tumors will be charted in far greater detail and clarity, eclipsing our current knowledge. And, as before Hanahan and Weinberg, , we continue to foresee cancer research as an increasingly logical science, in which myriad phenotypic complexities are manifestations of a small set of underlying organizing principles.

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