In the latest 2022 review, Hanahan proposes four emerging hallmarks and enabling characteristics: unlocking phenotypic plasticity, nonmutational epigenetic reprogramming, polymorphic microbiomes, and senescent cells³. He reviews existing evidence for the proposed emerging hallmarks, suggesting they might become incorporated into the core hallmarks of cancer in the future.

Unlocking phenotypic plasticity

Cancer cells unlock phenotypic plasticity - a capability restricted in normal cells – to enable different versions of disrupted differentiation, which can, in turn, facilitate cancer initiation and progression. Evidence suggests that phenotypic plasticity is a critical component of cancer pathogenesis³. Hanahan argues that such plasticity represents a discrete hallmark capability that differs in regulation and cellular phenotype from the previously established core hallmarks of cancer³.

In his review, he distinguishes three main types of phenotypic plasticity: dedifferentiation of mature cells back to progenitor states, blocked differentiation to freeze cancer cells in progenitor/stem cell states, and transdifferentiation into alternative cell lineages. All these plasticity types occur in multiple cancer types during tumor formation, progression, and therapy response.

Colon cancer is a typical example of dedifferentiation plasticity, with two transcription factors, HOXA5 and SMAD4, being highly expressed in differentiating epithelial cells and lost in advanced colon carcinomas. Examples of blocked differentiation include retinoic acid α nuclear receptor (RAR alpha) in acute promyelocytic leukemia, HDAC in acute myeloid leukemia, SOX10 in melanoma, and alpha-ketoglutarate in pancreatic cancer³. Finally, transdifferentiation is well described in pancreatic ductal adenocarcinoma (PDAC), where pancreatic acinar cells transdifferentiate into a ductal cell phenotype – the process involving two transcription factors, PTF1A and MIST1.

Nonmutational epigenetic reprogramming

Hanahan introduces the term “nonmutational epigenetic reprogramming” – an independent mechanism of genome reprogramming based on epigenetically regulated changes in gene expression³. This well-established epigenetic mechanism mediates embryonic development, tissue differentiation, and homeostasis.

Non-mutational epigenetic reprogramming can occur through microenvironmental mechanisms, such as hypoxia or epithelial-to-mesenchymal transition (EMT). Thus, hypoxia can lead to hypermethylation by reducing the activity of TET demethylases. EMT is responsible for mediating the reversible induction of cancer cell invasiveness at the borders of solid tumors.

Epigenetic regulatory heterogeneity plays an important role in non-mutational epigenetic reprogramming. A great example is the linker histone H1.0, which is dynamically expressed and repressed in subpopulations of cancer cells in several cancer types. Cancer cell populations with repressed H1.0 exhibit stem cell characteristics and an increased cancer-initiating capacity; they are also linked to poor prognosis in patients⁴.

All these examples support the hypothesis that epigenetic reprogramming can assist in the acquisition of hallmarks of cancer during cancer development and progression.

To read more about the role of various epigenetics targets and pathways in cancer, please refer to our cancer epigenetics guide.

Polymorphic microbiomes

Polymorphic variability in microbiomes – collections of microorganisms residing within our bodies – can significantly influence cancer phenotypes, development, and progression.

Hanahan builds the case for polymorphic microbiomes to represent a discrete enabling characteristic that impacts the acquisition of hallmarks of cancer, facilitating or protecting against different cancer types³. The most significant line of evidence involves the study showing the existence of cancer-protective and cancer-promoting microbiomes, which can modulate the incidence and pathogenesis of colon cancer. Also, the gut microbiome composition influences the immune system, affecting anti-tumor immunity and response to immunotherapy in patients with melanoma⁵.

Interestingly, the emerging hallmark of polymorphic microbiomes appears to intersect with those established hallmarks of genome instability and mutation and tumor-promoting inflammation.

Senescent cells

Cellular senescence is an irreversible mechanism of cell cycle arrest, which likely developed as a safeguard to maintain tissue homeostasis. This mechanism shuts down the cell division cycle, initiates cell morphology and metabolism changes, and activates senescence-associated secretory phenotype (SASP). Senescence can be triggered by various external and internal stimuli, including nutrient deprivation, DNA damage, damage to organelles and cellular infrastructure, and imbalance in cellular signaling.

Although senescent cells normally act as a defense against neoplasia, in some instances, they may stimulate tumor development and progression. Thus, SASP cytokines and growth factors released by senescent cells can be tumor suppressive or oncogenic in different contexts, cell types, and tumors⁶. In the latest review, Hanahan makes a convincing proposal to consider adding senescent cells to the functionally significant cells of TME.

Markers frequently used to identify senescent cells include senescence-associated beta-galactosidase and uPAR, one of the more recently described biomarkers, broadly induced during senescence⁷.

References

1. Hanahan, D., Weinberg, R. A. The hallmarks of cancer Cell 100 ,57-70 (2000)
2. Hanahan, D., Weinberg, R. A. Hallmarks of cancer: the next generation Cell 144 ,646-674 (2011)
3. Hanahan, D. Hallmarks of cancer: new dimensions Cancer Discov. 12 ,31-36 (2022)
4. Torres, C. M., Biran, A., Burney, M. J., et al. The liner histone H1.0 generates epigenetic and functional intratumor heterogeneity Science 353 (6307), (2016)
5. Spencer, C. N., McQuade, J. L., Gopalakrishnan, V., et al. Dietary fiber and probiotics influence the gut microbiome and melanoma immunotherapy resposne Science 374 (6575),1632-1640 (2021)
6. Rao, S. G., Jackson, J. G. SASP: Tumor suppressor or promoter? Yes! Trends Cancer 2 (11),676-687 (2016)
7. Amor, C., Feucht, J., Leibold, J., et al. Senolytic CAR T cells reverse senescence-associated pathologies Nature 583 (7814),127-132 (2020)