Hallmarks of cancer

The initial reductionist perspective of cancer, which regarded a tumor as solely composed of cancer cells, has been abandoned. Presently, it is acknowledged that a tumor is a malignant version of the tissue of origin, encompassing ‘regular’ tissue cells, blood vessels, and immune cells. These ‘normal’ cells in the tumor are altered by the cancer cells in such a way that they support tumor growth and prevent tumor immune destruction.

An overarching term for the non-cancer cell content of a tumor is named the tumor microenvironment and refers to the complex cellular and non-cellular components within and surrounding a tumor. Furthermore, tumor cells exhibit heterogeneity, with various genetic clones coexisting, and diverse differentiation statuses ranging from cancer stem cells to various lineages of differentiated cells.

The evolution of conceptual thinking on cancer and its underlying biological mechanisms is exemplified in the seminal work of Douglas Hanahan and Robert Weinberg. In their first groundbreaking review article titled “The Hallmarks of Cancer,” published in 2000, Hanahan and Weinberg conceptualized the major biological mechanisms that initiate and drive tumor formation (Hanahan & Weinberg, 2000). They identified six main biological processes orchestrating the transformation of normal cells into cancer cells: sustained proliferative signaling (cell growth), evading growth suppression, resisting cell death, enabling replicative immortality (unlimited growth), inducing angiogenesis (the growth of blood vessels into tumors to supply nutrients), and activating invasion and metastasis (see Figure 1).

Figure 1: The six hallmarks of cancer postulated in the year 2000 (taken from Hanahan & Weinberg, 2000).

About 10 years later, significant advancements in cancer research led to an updated version of the ‘Hallmarks of Cancer’ by the same authors with additional hallmarks. Two emerging hallmarks, deregulating cellular energetics and avoiding immune destruction, and 2 enabling processes, genome instability and tumor-promoting inflammation (see Figure 2). Also the complexity and heterogeneity of cancer is emphasized, highlighting the diverse genetic and epigenetic alterations that drive tumorigenesis and the interplay between cancer cells and the tumor microenvironment.

Figure 2: In the year 2011, 4 additional hallmarks of cancer were defined (taken from Hanahan & Weinberg, 2011).

Another updated perspective appeared in 2022 containing new dimensions of the hallmarks of cancer and are briefly described in the following (Hanahan 2022). Phenotypic plasticity and disrupted differentiation: This is proposed as a distinct hallmark capability. It highlights the flexibility of cancer cells to switch between different phenotypes and their disrupted differentiation, which affects their malignant behavior and therapeutic sensitivity. Non-mutational epigenetic reprogramming: Epigenetic changes play a crucial role in cancer development. These non-mutational alterations are now recognized as an enabling characteristic, because it allows reprogramming of gene expression that allows cells to adapt to changing conditions, including therapeutics . Polymorphic microbiomes: The microbiome’s influence on cancer is gaining attention as the population of bacteria in the gut is increasingly known to affect health and immune functions. It is considered another distinctive enabling feature. Senescent cells: Cells in a senescent state, originating from various tissues, are non-proliferating cells that are therapy resistant and secreted cancer promoting factors. They are now recognized as functionally important in the tumor microenvironment.

Therapeutic implications

The hallmarks of cancer provide a logical framework to understand cancer’s complexity. However, a primary objective of unraveling the underlying biology of cancer is to facilitate the development of new and better cancer treatments. Consequently, these hallmarks have not only deepened our understanding of cancer development and progression but also greatly advanced cancer medicine.

In parallel with cancer biology, Hanahan and Weinberg also summarize and discuss the therapeutic implications, including the development of targeted therapies aimed at disrupting specific hallmarks of cancer and the challenges posed by tumor heterogeneity and resistance to treatment. The authors explore the potential clinical applications, such as identifying biomarkers for early cancer detection, predicting patient prognosis, and guiding personalized treatment approaches. This is exemplified and illustrated in Figure 3.

The rapidly growing armamentarium of targeted therapeutics consists primarily of designed and developed small-molecules and antibodies directed against specific target proteins that are key for driving one or more specific hallmarks of cancer. This requires extensive multidisciplinary preclinical research and validation before these patient-tailored targeted therapies can be used in the clinic. Importantly, the use of these treatments will depend on patient tumor-specific genetic and/ or tumor microenvironment characteristics.

In Figure 3, the hallmarks and corresponding examples of a specific targeted therapeutic strategy are indicated. For example, EGFR (Epidermal Growth Factor Receptor) targeted therapy works by inhibiting the activity of the EGFR protein, which is a receptor found on the surface of cells. EGFR plays a crucial role in regulating cell growth, proliferation, and survival, and its overactivity or mutation is implicated in the development and progression of various cancers, including non-small cell lung cancer (NSCLC), colorectal cancer, and head and neck cancer.

Another example are the recent successes of immunotherapy. Immunotherapy works by harnessing the power of the immune system to recognize and destroy cancer cells. The immune system has the ability to identify and eliminate abnormal or foreign cells, including cancer cells, through a complex network of immune cells, signaling molecules, and checkpoints. In Figure 3, the checkpoint inhibitor CTLA-4 (cytotoxic T-lymphocyte-associated protein 4) is indicated. It targets proteins on immune cells or cancer cells that regulate immune responses. By blocking checkpoint proteins, the immune system’s ability to attack cancer cells is enhanced. Immunotherapy has shown remarkable success in treating various types of cancer, including melanoma, lung cancer, kidney cancer, bladder cancer, and certain types of lymphoma and leukemia. However, not all patients respond to immunotherapy, and it may cause side effects related to immune system activation, such as inflammation and autoimmune reactions.

Figure 3: Therapeutic Targeting of the Hallmarks of Cancer (taken from Hanahan 2022).

References and further reading:

• Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000 Jan 7;100(1):57-70.
• Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011 Mar 4;144(5):646-74.
• Hanahan D. Hallmarks of Cancer: New Dimensions. Cancer Discov. 2022 Jan;12(1):31-46. doi: 10.1158/2159-8290.CD-21-1059.
• Video: Interview with Doug Hanahan (2013).