The nature of cancer

1 Introduction

Cancer heterogeneity has been characterized with distinct differentiation states, metabolic status, and microenvironmental features, accounting for diverse responses to therapy. Recent view has proposed 14 hallmarks of cancer in order to provide a logical framework for the comprehensive understanding of the characteristics and processes responsible for malignant transformation and progression [1,2]. While these hallmarks portray the phenotypes of cancer, summarizing the underlying commonalities would offer new angle to revisit current anti-cancer regimens. In this perspective, based on the current understanding of cancer biology, we explore the common features that reflect the nature of cancer, namely pliability, hybridity, aggressivity, sociality and evolutivity, referred to hereinafter as PHASE (Fig.1). Each of these five elements of PHASE has been revealed to address the behavioral of cancer [1,2]. Yet, as traditional Chinese medicine uses the concept of Five Xing, including metal, wood, water, fire, and earth, to interpret the nature of all universal elements, these five elements of cancer PHASE are not irrelevantly separated; instead, they integrate and complement one another. PHASE coordinates all stages of cancer progression. Here, we describe each element of PHASE and discuss new concepts for the development of novel strategies to treat human cancers.

2 Pliability

Pliability of cancer refers to cancer cells possessing high plasticity that enables them to adapt to a variety of tissue environments and stressors. Cancer cells also dynamically switch between different pathological states to survive and advance. Pliability makes cancer flexible in the process of coping with harmful stressors, leading to a major reason for treatment failure.

Adaptation During cancer progression, cancer cells face a variety of growth and survival challenges, including hypoxic environment, nutrients deprivation, and space restriction, as well as hostile attack from both immunological surveillance and therapeutic treatments. Due to cellular pliability, tumor cells undergo molecular and phenotypic changes in order to adapt to these stressful challenges, thereby contributing to tumor heterogeneity, metastasis, and therapeutic resistance. For example, expressions of genes encoding cell-to-cell and cell-to-ECM adhesion molecules are altered during epithelial-mesenchymal transition (EMT)/mesenchymal-epithelial transition (MET) program [3]. Cancer cells take advantage of epithelial-mesenchymal pliability to adapt to different environments during the process of metastasis. Phenotype pliability is another example of adaptation, which enables cancer cells to resist both targeted therapy and immunotherapy. For example, in melanoma, although therapeutic resistance is partially caused by acquired mutations, mounting evidence points toward melanoma cells adapting to treatment pressures by “phenotype switching” [4].

Dynamics The status of a cancer cell is not constant and instead, changes dynamically in response to different stimuli. Tumor cells alternatively use either an “Accelerator” or “Brake” program in order to survive the existing situation. The “Accelerator” program switches on to induce a proliferative state when more cells are needed to colonize at both primary and metastatic sites. In contrast, the “Brake” program is chosen to lead to a dormant or a diapause-like state which the cancer cells will need to escape from therapeutic treatments or immune surveillance. For example, in EGFR mutant lung cancer, cancer cells enter dormancy through YAP-mediated transcriptional reprogramming of the apoptotic pathway in order to survive the combined EGFR/MEK inhibitor treatment [5]. In normal tissues, cellular senescence is a stress-response cell-cycle arrest program that is usually irreversible and prevents malignant transformation. In comparison, tumor cells have the capacity of full-featured senescence reversibility, meaning that they are poised to re-enter the cell cycle when they are in a pre-senescent or early senescent state. When switching to a senescent state, tumor cells are able to survive during chemotherapy and increase their stemness, endowing them with enhanced plasticity and higher tumor-initiating potentials when they re-enter the cell cycle [6,7].

The pliability state of cancer cell is nonpersistent and occurs when cell changes its identity or function, such as the process of cancerous transformation, therapeutic resistance, or metastasis. Cancer cell in pliability tends to revert to a progenitor or stem cell stage which is similar to those observed in early stage of lineage development. The acquisition or maintenance of pliability state is mainly driven by a cellular intrinsic mechanism, including genetic aberrations, non-mutational epigenetic or metabolic reprogramming, or aberrant signaling regulation. For example, in the context of mutant KRAS-driven lung adenocarcinoma, Lkb1 inactivation has been shown to induce both metabolic and epigenomic reprogramming that promotes tumor plasticity, enabling squamous transformation and therapeutic resistance [8,9]. In addition, either activation of AKT signaling pathway or aberrant activity of MYC and SOX families of transcriptional regulators has been implicated as being inducers of pliability cell phenotypes [10]. Besides intrinsic factors, the external stimuli such as cytotoxic treatment or nutrient stresses also influence tumor pliability through integrating with cellular intrinsic responses. For example, basal cell carcinomas treated with a Hedgehog inhibitor undergoes a plastic, stem-like phenotype which is enabled by a mostly permissive chromatin state accompanied by both rapid Wnt pathway activation and reprogramming of super enhancers, that drive activation of key transcription factors involved in cellular identity [11]. Thus, the cancer pliability has a key role in major events of cancer development including tumorous transformation, metastasis, and therapeutic resistance.

3 Hybridity

A well-differentiated normal cell usually acquires a definitive developmental state to perform certain specific tasks. In contrast, a tumor cell may lose its identity and acquire a hybrid state, which exhibits multiple phenotypic features or multipotency. In the process of adapting to an unfavorable environment or pressure, cancer cells can acquire some of the phenotypes and functions of other types of cells, leading to chimeras. In addition, unlike fully differentiated cells, cancer cells integrate features of cells at different stages of differentiation and development, or of different molecular and metabolic phenotypes, known as versatility. The hybridity of cancer cells is positively correlated with their malignant potential by providing a mechanism for their adaptation to various stressors and environments.

Chimerism The chimerism of cancer cells is characterized by acquiring the profiles and phenotypes of other cell types, beside their own phenotypes. Chimeric cells play an important role in cancer progression. For example, cancer cells express synaptic genes, form connections with neurons, and use neuron-like signaling to support tumor growth and invasiveness in the brain. Functional bona fide chemical synapses between presynaptic neurons and postsynaptic glioma cells have been observed in gliomas [12]. In addition, in order to adapt to the metastatic environment after spreading from the primary site, tumor cells acquire some of the features and functions of the host cells. Breast-to-brain metastatic cells can form pseudo-tripartite synapses with neurons that provide a source of the neurotransmitter glutamate, thereby activating NMDAR signaling that stimulates tumor growth in the brain [13].

Versatility Well-differentiated normal cells generally have well-defined identities and functions, while cancer cells acquire distinct phenotypes at different stages of differentiation. This endows tumor cells with an enhanced ability to adapt, thereby promoting their aggressiveness and therapeutic resistance. For example, cancer cells can exhibit both mesenchymal and epithelial characteristics, forming a hybrid E/M phenotype known as partial EMT. Notably, the hybrid E/M phenotype may be coupled with a hybrid metabolic state in which both glycolysis and OXPHOS can be used to flexibly utilize a variety of nutrients and efficiently generate energy. Thus, the hybrid phenotype confers advantages to cancer cells for their survival, invasion, and metastasis, as well as therapeutic resistance [14]. Indeed, the versatility of tumor cells may positively correlate with their malignant potentials [15].

The hybridity state represents a specific phenotype or function of cancer cell losing its original distinct lineage identity but gaining a mosaic-like composition. The hybridity of cancer cells varies in phenotype or composition depending on the context they are in. Therefore, the hybridity state is obtained from the integration of both environmental and intrinsic cues. For example, the formation of neural mimicry in glioblastoma and breast cancer brain metastases depends on the rich neuronal environment in the brain. Similarly, hybrid EMT state or hybrid (glycolysis and OXPHOS) metabolic state has been usually observed in initial metastatic and super-invasive tumor cells [16,17]. In the cells that initiate tumor metastasis, the EMT related gene ZEB1 promoter exhibits a bivalent state that contains both transcription-repressive (histone H3 trimethylated at K27 (H3K27me3)) and transcription-permissive (histone H3 trimethylated at K4 (H3K4me3)) modifications. This primed bivalent state can facilitate rapid modification of gene expression patterns for interconversion between epithelial and mesenchymal phenotypes. Thus, the hybrid state confers versatility to cancer cells and enables them for rapid switch between multiple phenotypes in response to environmental cues, making them in the most heterogeneous state for survival.

4 Aggressivity

Aggressivity of a tumor is reflected in two aspects. One is “step out” as tumor cells frequently invade adjacent tissues or metastasize to other sites. The other is “bring in,” which is a process where tumor cells actively recruit various types of other cells into the tumor tissues for inducing angiogenesis, innervation, and immunosuppression, thereby remodeling the tumor microenvironment. This aggressive nature allows cancer cells to survive and progress even in a variety of hostile conditions.

Invasion (step out) Tumor cells not only have a strong invasive ability, but also can reprogram their microenvironments to promote their growth and spread, which is one of the reasons that tumors are difficult to treat. As one of the most aggressive representatives, glioblastoma invades the healthy brain by spreading like a fungal network. Notably, whole-brain colonization is fueled by glioblastoma cells that hijacks neuronal mechanisms for brain invasion [18]. As a result, these cancer cells can hardly be completely removed surgically, and are resistant to both chemotherapy and radiotherapy. In addition, tumor spread of invasive front melanoma cells occurs via an immunomodulatory secretome. In this scenario, melanoma cells control their associated macrophages to support an abnormal vasculature that ultimately facilitates metastasis [19].

Recruitment (bring in) Tumor cells recruit or “educate” various types of cells such as nerve cells, vascular cells, and immune cells. This creates an accomplice for the tumor, which provides fuel to promote tumor initiation and progression. For example, the innervation has been found in a variety of solid and hematological malignancies. Tumor cells reactivate nerve-dependent developmental and regenerative processes to promote their growth and survival [20]. Moreover, tumor cells with high plasticity transdifferentiate into a neuron-like population or vascular pericytes that provide functional support for cancer progression [21].

The cancer aggressivity state is often manifested as a demand-driven functional specialization state in a subpopulation of cancer cells that outgrow the equivalent surrounding competitors. When cancer cells demand to invade for metastasis or compete nutriments for survival, a subset of tumor cells is in aggressive state. This aggressivity may be turned off in some other situations when cancer cells enter dormancy to avoid cytotoxic activity. The cancer aggressivity can be obtained and maintained by modifications within the tumor cell itself or its microenvironment. For example, the EMT process has been linked with increased aggressiveness of tumor cells [22]. On the one hand, mutations or epigenetic repression of the epithelial genes such as CDH1 result in enhanced cell mobility and EMT which can be observed in invasive front cancer cells. On the other hand, dysregulation of intracellular and extracellular signals including TGF-β, Sonic hedgehog, and Notch pathways, cytokines such as IL-8, IL-6, and TNF-α, or tumor cell interactions with extracellular matrix components can also promote EMT. Thus, the aggressivity endows cancer cells with a variety of malignant behaviors that promote tumor progression.

5 Sociality

Tumor tissues consist of different cell populations, where cancer cells communicate with various other types of cells, as well as microorganisms such as bacteria in their microenvironments. These components all cooperate to create a unique ecosystem that functions as a well-organized society. Each societal member exercises a distinct role in maintaining the survival and propagation of the core element, the cancer cells. To view a tumor as an intricate ecological society helps to conceptualize and ferment more precise diagnoses and treatment strategies for cancer therapy.

Coordination Within a tumor, both cancer cells and other types of stromal cells coordinate with one another to fulfill distinct roles. These role members form functional sub-populations, to name but a few, “stem and propagating,” “leader and subordinate,” “police and surveillant,” and “bystander” populations. These different subpopulations cooperate or restrain one another, and the outcome plays an important role in tumor progression. For example, in cutaneous squamous cell carcinoma (cSCC), an elite population known as the tumor-specific keratinocytes (TSKs) are located at the leading edge of tumor. These cells guide not only their metastatic potential but also help them evade the immune system. Indeed, the TSKs act as a hub for intercellular communication that ultimately creates the program that designs and coordinates cancer progression [23].

Communication Tumor tissues are composed of various types of cells and microorganisms, which all communicate closely with one another through cytokines, metabolites, exosomes, and other substances. These communication messengers induce immunosuppression, provide nutrition, promote invasion and metastasis, thus creating an ecological microenvironment for the survival and progression of tumor cells. For example, breast cancer cells secrete extracellular-vesicle-encapsulated miR-105, which activates MYC signaling in cancer-associated fibroblasts (CAFs) to induce a specific metabolic program. The CAFs then enhance glucose and glutamine metabolism to provide fuel for adjacent cancer cells when nutrients are insufficient. Meanwhile, the CAFs detoxify metabolic waste when nutrient levels are low and when metabolic by-products begin to accumulate [24].

The sociality of cancer is an ongoing state maintained by all tumor cells and their environmental elements. The cancer sociality is mainly achieved by signal transduction mediated by receptor ligation, endocytosis or the mechanical force of cell-cell contact. For example, tumor-CAFs crosstalk through TGF-β, PDGF, IL-6, chemokines and their cognate receptors that trigger signaling activation and promote their malignancy. Similarly, the Wnt-driven mammary cancer is another example of intratumor cooperation that the basal subclones will recruit heterologous Wnt-producing cells to rescue Wnt pathway activation and drive relapse when the luminal subclones which secrete Wnt1 are inhibited [25–27]. Thus, the cancer sociality enables tumors to construct a complex and dynamic ecosystem that poses great challenges for cancer treatment.

6 Evolutivity

Genomic instability embodies cancer cells with the ability to acquire an elevated rate of somatic aberrations, ranging from positional mutation to chromosomal aneuploidy. Cancer progression may be viewed as a somatic evolutionary process for adapting to pathological stressors. Indeed, cancer is a dynamic disease. Every step of multistage carcinogenesis, from tumor genesis to metastasis, is driven by evolutionary mutations and selection processes that shape the cancer genome and play critical roles that endow tumors with the heterogeneity and the therapeutic resistance [28,29]. Viewing cancer from an evolutionary perspective helps us to understand the reason for cancer heterogeneity and therapeutic resistance.

Heterogeneity Heterogeneity of tumors refers to more than just spatial heterogeneity, including both intra-tumor and inter-tumor heterogeneity. It also includes temporal heterogeneity, including variations between primary and recurrence or metastasis, both pre- and post-treatment [30]. The tumor heterogeneity and cancer evolutivity cooperate in mutually beneficial manner. On the one hand, the heterogeneity provides diverse genetic and epigenetic material from selection to evolution [29]. On the other hand, both linear and branched tumor evolution result in heterogeneous tumors, which has been found in various tumor types, including breast, prostate, pancreatic and clear cell renal cell carcinoma [30].

Therapeutic resistance Therapeutic resistance is a key challenge in cancer medicine, which is fostered by cancer evolutivity. Mutually, cancer treatments result in the accelerated evolution of the cancer genome. For instance, cancer cells from patients who received targeted therapies display much higher levels of DNA damage than pre-treatment samples, even when such treatments do not directly damage DNA. Indeed, a broad range of cancers, including melanoma, pancreatic cancer, sarcomas, and breast cancer, generate a high number of errors during mitotic DNA replication when exposed to cancer treatments. Additionally, like ancient single-celled organisms, such as bacteria, cancer cells exposed to therapeutic drugs undergo an evolutionary process called stress-induced mutagenesis, which leads to drug resistance [31].

The evolutivity of cancer is a persistent state that drives temporal changes in fitness and diversity of cancer cells. The cancer evolutivity is mainly obtained and maintained by intracellular mechanisms. Cancer cells sustain to proliferate, resulting in accumulation of mutations. The mechanisms that maintain genomic stability and integrity including DNA checkpoints and repair machinery, mitotic checkpoints or telomere protection are usually compromised in cancer cells, which promote cancer evolution. For example, defects in the guardian of the genome TP53 or DNA repair gene BRCA1/2 are common events in cancer cells [1]. Besides intrinsic mechanisms, selective pressures such as therapeutics, immunity, and environment can also promote cancer evolution by increasing mutations and genomic instability. Thus, the cancer evolutivity acts as a driving force that enables tumor dynamic evolvement to promote cancer progression.

Each of the five states plays a key role respectively in different stages of cancer. For example, evolutivity and pliability are required in the process of malignant transformation with phenotype transition, while hybridity, aggressivity, and sociality are essential for tumor survival and expansion. Moreover, the five states of cancer promote each other mutually: the pliability generates hybridity, the formation of hybridity requires transition from pliability, the hybridity causes aggressivity, aggressivity establishes the sociality, sociality shapes the evolutivity, and the evolutivity closes the circle by creating pliability. For example, in the EMT process, cancer cells undergo a pliability state that changes from an epithelial state to a hybrid E/M state. The hybrid E/M cancer cells obtained aggressivity which engaged in collective migration in vitro and generated more circulating tumor clusters in vivo [22]. Similarly, the aggressive cancer cells play a dominant role in shaping cancer society through interaction with the surrounding niche elements by educating or competing with other cells [32]. In accordance, the cancer society provides selection stress such as immune surveillance and nutrition competition for cancer evolutivity. As a close loop, the evolutivity of cancer generates oncogenic mutations such as KRAS and PIK3CA that promote pliability [33–35]. Thus, the five PHASE (states) make cancer a self-organized homeostatic system.

7 PINE

Our bodies, from a cell to the whole organism, must be maintained in a homeostatic state to function properly, which is known as “YinYang” in Chinese. The maintenance of homeostasis at all levels, from cellular organelles to the whole organism relies on multiple systemic and molecular mechanisms of positive or negative feedback regulation, such as body temperature, blood glucose, and circadian rhythm maintenance. Disruption of homeostasis in both cells and body system will affect each other, creating a vicious cycle.

As increasing evidence has proven that cancer is a systemic disease, we consider that cancer is a disease caused by stress that disrupts normal physiological homeostatic process. On the whole, the systemic homeostasis is maintained by psychological, immunological, neural, and endocrine systems, referred to as PINE. The four elements of PINE coordinate with one another to maintain physiological stability. Dys-regulation or defect in PINE leads to disrupts of homeostasis that promote tumorigenesis. For example, the chronic psychological stress leads to systemic homeostasis perturbations by impairing the neuroendocrine and immune systems and contributes to the development of cancers [36–38]. Both psychological adjustment and drug intervention to maintain mental health have shown remarkable effects in the treatment of cancer [36,39]. Another good example is immune checkpoint inhibitors targeting the dysfunctional immune system, specifically anti-CTLA4 and anti-PD-1 antibodies, which have revolutionized the management of many cancers, particularly advanced melanoma, where nearly half of patients achieve tumor regression and long-term lasting cancer control compared to less than one tenth historically [40].

We thus propose that the cancer treatment strategies should target the cause of cancer, by establishing the goal and evaluation index as restoration of the normal functional coordination of PINE, which would have profound implications for future cancer research and treatment.

8 Conclusions

Based on above proposed five nature of cancer, treatment targeting the tumor itself is often difficult in achieving the goal of complete elimination of cancer. Thus, we should focus not just on the tumor itself, or its microenvironment, but also the cause of cancer.

As the loss of PINE homeostasis is considered as the overall environment suitable for cancer initiation and progression, to treat cancer effectively, on the one hand, one has to address the tumor (treating the symptoms) and on the other hand, to restore “PINE” and physiological homeostasis (treating the root). Besides therapeutic approaches, this includes lifestyle changes, improvement of our mood and mental health. Only then we can better constrain cancer and its outcomes (Fig.2).

9 Three outstanding questions

9.1 Cancer may not be eliminated, but can it be controlled?

The five elements of cancer embodied by “PHASE” elucidate how cancer may easily adapt to different environments and stressors. As such, the goal to completely eliminate cancer seems challenging. Almost all current cancer therapies lead to resistance. The goal of treatment may be to control, but not eliminate cancer.

9.2 The harder cancer is hit, the worse it comes back?

In the process of treating cancer, drugs may be effective in suppressing the tumor initially. However, once resistance occurs, the disease tends to progress more rapidly. Based on the evolutivity and pliability of cancer, presumably, the harder cancer is hit, the more it bounces back. How anti-cancer drugs may be used to control cancer, while slowing down resistance, remains to be explored.

9.3 Is cancer the end result of a disturbance in the physiological homeostasis?

Cancer develops not only because of the transformation of normal cells, but also the disruption of the protective systems that can no longer defend against tumors. During healthy homeostasis, psychological, immunological, neural, and endocrine systems (PINE) coordinate to prevent cancer initiation and progression. That is why immunotherapy has achieved some encouraging success in cancer treatments. In a sense, cancer is a disease that accumulates from the breach of PINE, more than just a single mutational event.

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