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Landmark Paper on 'Hallmarks of Cancer' Leads the Way in Oncology Research
In 2000, Professor Douglas Hanahan and Professor Robert A. Weinberg from the Massachusetts Institute of Technology jointly published the first version of “The Hallmarks of Cancer” in the journal CELL, describing the six major hallmarks of tumor malignancy. This review has become one of the most cited articles in the history of CELL.
The six major hallmarks described in the first version of “The Hallmarks of Cancer” include:
Schematic diagram of the six major physiological characteristics of tumor malignancy in the first version
1. Sustaining proliferative signaling
Cancer cells can produce growth factors autonomously and are self-sufficient; they can also stimulate normal cells to upregulate growth factors, which then provide feedback to themselves. Negative feedback regulation normally serves to attenuate various types of signals, and the failure of this negative feedback mechanism in tumor proliferation signaling leads to uncontrolled growth.
2. Evading growth suppressors
The two classic proliferation inhibitors —— TP53 and RB, act as two important switches for growth suppression. TP53 receives intracellular inhibitory signals, while RB transduces extracellular inhibitory signals. The loss of these proteins can lead to cellular transformation into tumors.
3. Activating invasion and metastasis
Cancer cell transformation begins with local invasion, followed by infiltration into surrounding blood and lymphatic vessels. Through transport via the lymphatic or blood system, cancer cells escape from these vascular networks and enter the parenchyma of distant tissues (extravasation), forming small cancer cell nodules (micro-metastases). Eventually, these micro-metastatic lesions grow into macroscopic tumors.
4. Immortalization
To achieve unlimited proliferation, cells must overcome two proliferative barriers: senescence and crisis/apoptosis, including cell death. These barriers theoretically constitute an important anticancer defense system. Telomeres control the number of generations a cell can replicate, and telomerase, a specific DNA polymerase, is highly expressed in immortalized cancer cells, allowing them to proliferate indefinitely.
5. Inducing angiogenesis
Evidence suggests that the angiogenic switch is controlled by angiogenic factors that can either induce or inhibit angiogenesis. Some angiogenic regulatory factors emit signaling proteins that act on stimulatory or inhibitory receptors on the surface of vascular endothelial cells. The well-known angiogenic inducer is Vascular Endothelial Growth Factor A (VEGF-A). Oncogenic signaling can upregulate the expression of the VEGF gene, thereby promoting tumor angiogenesis.
6. Resisting apoptosis
Tumor cells have evolved a series of mechanisms to limit or evade apoptosis. The most common is genetic alterations in TP53, which affect the p53 cell cycle and limit or evade apoptosis. Another method involves upregulating anti-apoptotic factors (e.g., Bcl-2, Bcl-xl), downregulating pro-apoptotic factors (e.g., Bax, Bim), increasing the expression levels of survival signals (e.g., Insulin-like Growth Factor 1/2), or shortening the extrinsic ligand-induced death pathway. Tumors can also limit or evade apoptosis through these mechanisms.
A decade later, the second edition “Hallmarks of Cancer: The Next Generation” was introduced, adding two new hallmarks and two enabling characteristics to the original list.
The ten hallmarks of cancer in the second version
Two new hallmarks:
1. Immune evasion
The fundamental argument that antitumor immunity serves as an important barrier to tumor formation and evolution in the human body has led to the recognition of immune evasion as an emerging hallmark. With the advent of precise identification of immune cell markers, nearly every tumor lesion contains immune cells detectable by specific antibodies. Moreover, many types of antitumor responses are accompanied by immune evasion.
2. Reprogramming energy metabolism
Uncontrolled and frequent cell proliferation is the essence of neoplastic diseases. This not only includes the downregulation of cell proliferation control but also the adaptation of corresponding energy metabolism to meet the energetic demands of cell proliferation and differentiation. The widespread alteration of energy metabolism in cancer cells, which has been established as a hallmark of cancer, is associated with many other cancer-related characteristics.
Two enabling characteristics:
1. Genomic instability and mutations
Although there is significant variation in genomic alterations among different tumor types, numerous defects in genomic maintenance and repair have been demonstrated in human tumors. These defects are accompanied by widespread genomic instability and nucleotide sequence alterations.
2. Tumor-promoting inflammation
In some cases, inflammation in the early stages of tumor evolution is clearly evident and has the capacity to promote the development of early tumors and their progression to mature cancers. Additionally, inflammatory cells can release chemicals, particularly reactive oxygen species, which have mutagenic effects on surrounding cancer cells and can accelerate the transformation of cancer cells to a more malignant state. Similarly, since inflammation aids in the acquisition of core hallmark capabilities, it is considered an enabling characteristic. Cells related to this enabling characteristic will be described in the context of the tumor microenvironment below.
Another decade later, the article “Hallmarks of Cancer: New Dimensions” added four new hallmarks based on the previous two versions.
The fourteen hallmarks of cancer in the third version
1. Unlocking phenotypic plasticity
During organogenesis, cell differentiation is mostly opposed to proliferation. Increasing evidence suggests that to escape terminal differentiation, cancer cells unlock phenotypic plasticity through dedifferentiation, inhibition of differentiation, and transdifferentiation.
2. Non-mutational epigenetic reprogramming
Genomic instability and mutations are fundamental components of cancer formation and pathogenesis. In addition, there is another distinct mode of genomic reprogramming involving pure epigenetic regulation of gene expression changes, known as “non-mutational epigenetic reprogramming.” This has been established as a core mechanism mediating embryonic development, differentiation, and organogenesis.
3. Polymorphic microbiome
The diversity and variability of the microbiome, as a frontier area of current biomedical research, are symbiotic with external environment-exposed barrier tissues (especially the epidermis and internal mucosa), particularly the gastrointestinal tract, lungs, breasts, and urogenital system. The ecosystem established by the resident microbiome has profound effects on health and disease. For tumors, the polymorphic variation of the microbiome among individuals in the population may have a profound impact on cancer phenotypes.
4. Senescent cells
In some cases, senescent cells can stimulate tumor development and malignant progression to varying degrees. The primary mechanism is the Senescence-Associated Secretory Phenotype (SASP), which transmits signaling molecules to nearby living cancer cells and other cells in the Tumor Microenvironment (TME) through paracrine signaling to convey hallmark capabilities.
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March 10, 2025
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