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All issues Volume 6 (2025) Vis Cancer Med, 6 (2025) 7 Full HTML
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Vis Cancer Med
Volume 6, 2025
Article Number 7
Number of page(s) 5
DOI https://doi.org/10.1051/vcm/2025006
Published online 03 May 2025

© The Authors, published by EDP Sciences, 2025

Licence Creative CommonsThis is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Life and death represent enduring themes in life sciences, with the dynamics of cellular life and death serving as pivotal aspects in tumor biology. Before the 1990s, the scientific community predominantly focused on tissue differentiation and cell proliferation in their understanding of cancers. The unveiling of the anti-apoptotic gene bcl-2 in follicular B cell lymphoma marked a significant turning point in cancer research, heralding an era that delves into the interplay between cell death and tumorigenesis. As research advances, it has been highlighted the existence of prevalent misunderstandings and misconceptions in this domain. This article offers a theoretical exploration of pertinent issues from the vantage points of pathology and tumor biology.

Pathological “necrosis” differs from cytological necrosis

Necrosis is a concept that has long been present in pathology, referring to the death of large amounts of cells and the breakdown, coagulation, or liquefaction of tissues. Sometimes, smaller necrotic areas only exhibit secondary reactions following cell death, such as the focal aggregation of lymphocytes and tissue cells seen in piecemeal necrosis of the liver.

Another meaning of necrosis is that it is a form of cell death. In various textbooks such as “Cell Biology,” “Pathophysiology,” and “Pathology,” necrosis is primarily defined as a form of cell death. Historically, necrosis and apoptosis have been considered as two opposing modes of cell death. Necrosis is considered a form of “murder”, non-programmed death, morphologically characterized by pale cytoplasm and cellular swelling, known as oncosis. In contrast, apoptosis is viewed as cell suicide, programmed death, featured by cytoplasmic shrinkage, termed shrinkage-induced cell death [1]. Subsequently, regulated necrosis (necroptosis) has been identified [2]. It has been suggested to replace the term “necrosis” with “oncosis” to refer to the form of cell death, while using “necrosis” to specifically describe post-death degradation; however, oncosis is rarely used in mainstream literature and textbooks.

Besides necrosis and apoptosis, there are two other distinct forms of cell death: ferroptosis caused by lipid peroxidation due to Fe2+ accumulation and pyroptosis which is related to inflammation [3, 4].

Regardless of the mode and mechanism of cell death, these processes ultimately manifest pathologically as necrosis. Therefore, in pathology, “necrosis” merely represents the outcome of cell death and tissue destruction. Any form of cell death can eventually present as “necrosis” pathologically (Figure 1).

thumbnail Figure 1

Apoptosis vs. pathological necrosis. This image was taken from a breast cancer case. The area to the left of the yellow line is pathologically called necrosis, while the nucleated cells indicated by the arrows are undergoing apoptosis. This illustrates that the term “necrosis” in pathology often refers to extensive cell death, which can include both apoptosis and other forms of cell death. Bar = 20 µm.

The distinction between pathological necrosis and the necrotic mode of cell death should be clearly elucidated to avoid confusion. For instance, in chemotherapy of cancer, cells die through apoptosis [5]. However, pathological reports on the effects of neoadjuvant chemotherapy may describe it as necrosis. This distinction is crucial to prevent confusion among clinicians and researchers who are unfamiliar with pathology. The simple explanation is that apoptosis represents the process of cell death, while necrosis is the final pathological result (Figure 1).

Autophage is a behavior of self-rescue, and plays an inhibitory role in tumorigenesis and progression

During the Spring and Autumn Period in ancient China, Duke Wen of Jin, known as Chong’er, and his companions found themselves stranded outdoors, enduring days of starvation that led to dizziness and lightheadedness. In a remarkable display of altruism, one of his followers, Jie Zi-tui, sacrificed his own leg flesh by cooking it to stave off starvation for the group. This poignant tale exemplifies a classic instance of human resilience in the face of environmental adversity, akin to autophagy. Beyond extreme measures like self-cannibalism in times of famine, actions such as a warrior severing his own arm to survive poisoning or medical amputations for necrotic limbs and malignant tumors also illustrate the essence of autophagy as a form of “self-rescue.”

Autophagy is a cellular process in which cells engulf and digest their own structures or similar components, mirroring human autophagy, and is often induced by environmental stress. The primary goal of autophagy is self-preservation, rather than self-destruction. While autophagy can potentially culminate in cell death, its overarching effect is the extension of cells’ average lifespan. Following the principle of the inverse correlation between lifespan and reproductive capacity, prolonging the average lifespan of cells inherently restrains their proliferation [6, 7].

Multiple roles of autophagy in tumorigenesis and cancer progressions have been reported [8, 9]. In general, autophagy exerts a suppressive effect on tumor occurrence and development. As an example, Beclin1 plays a vital role in promoting cellular autophagy. Disrupting Beclin1 signaling inhibits autophagy in cells, leading to an increase in cancer development [10]. However, current mainstream theories and perspectives find it highly challenging to reconcile, resulting in numerous contradictory and puzzling explanations. Some argue that since autophagy ultimately extends cell lifespan, it should promote cancer growth. The paradox of tumor suppression despite autophagy’s potential to reduce cell death arises from a fundamental misunderstanding of the interplay between cell death and tumorigenesis.

Both apoptosis and necrosis are markedly increased in cancer

In the 1980s, the anti-apoptotic gene bcl-2 was discovered in follicular B-cell lymphoma (FCL) [11] and was subsequently found to be overexpressed in a variety of cancers. Consequently, it was proposed that proteins with anti-apoptotic properties as a novel category of oncogene [12]. It was further suggested that cancer cells acquire “anti-apoptotic” traits [12, 13]. However, this remains a hypothesis rooted in the speculation of molecular biologists, reasoning that a decrease in cell death combined with increased cell division leads to an overall increase in the amount of cells, promoting tumor growth and facilitating its progression. This viewpoint also aligns with the notion of “Darwinian monster” entities that evolve continuously through the processes of “gene mutation – natural selection, further mutation – further selection,” resulting in the emergence of immortal and forever proliferating cells.

The “resistance to apoptosis” as a hallmark of cancer not only contradicts established facts but also challenges logical reasoning. In 2014, a collaborative publication by nine pathology professors from seven universities of China definitively stated that resistance to apoptosis is not a defining trait of cancer [14]. On the contrary, pathologists noted that apoptosis is relatively uncommon in benign tumors but significantly elevated in cancers. Furthermore, as the malignancy of cancer increases, so does the occurrence of apoptosis. Highly malignant neoplasms like Burkitt’s lymphoma and retinoblastoma often display the characteristic “starry sky” pattern, which are formed by histiocytic engulfing numerous apoptotic cancer cells (Figure 2). Due to the prevalent belief in the concept of “cancer cells being resistant to apoptosis”, few publications have recognized apoptosis as an indicator of malignancy. Nevertheless, many experienced pathologists do use it as a diagnostic criterion for malignancy. In addition, the presence of tumor necrosis as a sign of malignancy is universally acknowledged. Logically, pathological necrosis arises from extensive apoptosis as we discussed above, therefore, if cancer cells are resistant to apoptosis, the occurrence of tumor necrosis would become questionable. While it is true that apoptosis is notably reduced in low-grade follicular lymphoma (FCL) compared to normal lymphoid follicles’ germinal centers, concluding that tumor cells are anti-apoptotic is not only logically insufficient but also reflects a lack of understanding of biological behavior of follicular lymphoma. In FCL cases, there are distinctions between low-grade and high-grade variants; low-grade FCL often shows abnormal bcl-2 overexpression due to translocation to the downstream of IgH gene, inhibiting cell apoptosis in germinal centers. Conversely, high-grade FCL typically lacks this translocation and bcl-2 overexpression, with both cellular apoptosis and proliferation rates significantly higher than in low-grade FCL. Consequently, if we compare the same histological type of lymphoma, bcl-2 overexpression leading to resistance to apoptosis encourages tumor cells to exhibit more benign biological behavior. Notably, low-grade FCL can achieve long-term survival without necessitating chemotherapy.

thumbnail Figure 2

Apoptosis, Bcl-2 expression, and cell proliferation. The left panel shows a case of Burkitt lymphoma, characterized by extensive apoptosis, which creates a “starry sky” appearance due to phagocytosis of cell debris by the macrophages in H.E staining. Notably, Bcl-2 is not expressed, and the tumor proliferation index is extremely high. The right panel depicts a case of low-grade follicular lymphoma (FCL), in which apoptosis is rarely observed. Bcl-2 expression is abnormally high due to its dislocation to the neighborhood of immunoglobulin heavy chain (IgH), resulting in a significantly lower tumor proliferation index. All the pictures are the same magnification. Bar = 60 µm.

Factors which promote cell death also foster cancer

Cell death is closely linked to the malignancy of tumors, which begs a fundamental question: does cell death, regardless of its form, facilitate or hinder the initiation and progression of cancer? Chinese scholars have definitively stated that cell death fosters the emergence and advancement of cancer [14, 15]. European researchers have long noted an increase in apoptosis in cancer cells, correlating positively with the degree of malignancy [16, 17]. Nevertheless, the acknowledgment of the role of apoptosis in promoting cancer is a relatively recent revelation [18–20]. Yet, most explanations present a paradox. It is generally taken that although apoptosis reduces cell numbers and thus inhibits cancer; it also stimulates tumorigenesis by creating an inflammatory environment. This contradictory stance reflects internal conflicts which violates logical principles like non-contradiction and the law of excluded middle.

To resolve this theoretical contradiction, one must first discard the notion that apoptosis, by reducing cell numbers, inhibits cancer. In the biological realm, life and death are intricately intertwined. Excessive death inevitably spurs reproduction, with the resulting increase surpassing deaths; otherwise, populations cannot thrive. This interconnectedness spans various levels from genes to cells to animal populations, including humans.

Genetically, c-myc, known for its potent oncogenic effect, plays a dual role in both promoting apoptosis as well as proliferation. Bax, a classical pro-apoptotic gene that forming dimers with bcl-2 to inhibit its function, was initially viewed as a tumor suppressor [21]. Interestingly, Bax was later found to promote cancer by the same research group [21, 22]. The Fas receptor responds to external apoptotic signals triggering cell apoptosis. In liver cancer cells, knocking down Fas expression inhibits cell growth. Conversely, Fas overexpression accelerates liver cancer cell proliferation significantly [23]. The HBx protein induced by hepatitis B virus infection exhibits a clear pro-apoptotic effect, yet it plays a pivotal role in liver cancer initiation [24, 25]. The concept of the “ideal tumor suppressor gene” promoting apoptosis while inhibiting cell proliferation is theoretically implausible. We can get this conclusion by a thought experiment. If this gene were to be transfected into cultured cells, once it was expressed, the cells would be unable to proliferate but initiating cell death processes, thus observing its expression and function would be impossible. From an evolutionary standpoint of natural selection, organisms with such ideal tumor suppressor genes would likely become extinct and thus such genes not preserved through evolution.

Examining carcinogenic factors reveals that all carcinogens, whether physical, chemical, or biological, all promote apoptosis instead of being anti-apoptotic or contributing to cellular longevity. Conversely, factors protecting cells within organisms and inhibiting apoptosis exhibit tumor suppressing effects. For example, autophagy naturally extends cell lifespan acting as an anti-cancer factor. Additionally, p53 rapidly overexpresses under stress stimuli to safeguard cells and exhibits anti-cancer effects. Bcl-2, a typical anti-apoptotic gene strongly inhibits cell proliferation both in vitro and in vivo [26]. Clinically, over expression of Bcl-2 in cancer cells is generally associated with more favorable prognosis. Transgenic animal experiments have shown that overexpression of Bcl-2 retarded tumor development [27, 28]. Therefore, it is more reasonable to categorize Bcl-2 as a tumor suppressor instead of proto-oncogene. Logically speaking, designating both c-Myc and Bcl-2 as oncogenes despite of their opposing functions introduces contradictions and increased the irrationality of the theoretical system.

Recent findings on programmed necrosis (necroptosis), pyroptosis, and ferroptosis further support that cell death promotes cancer development and metastasis [2–4]. Although it has been widely claimed these various forms of cell death play dual roles in promoting and inhibiting cancer, they fundamentally foster cancer development. The so-called cancer-inhibiting effects stem from the notion of reducing cell amounts by cell death. As evidenced in this article’s argumentation, it is precisely the increased cell death that propels cancer initiation and progression.

Theoretical implications – reducing cellular apoptosis as a strategy of cancer treatment

The positive role of cell death in cancer progression raises an important question: How should cancer be treated based on this theory? Can cancer be managed by reducing cell death? The answer is yes. In fact, this approach addresses a long-standing question about how to prolong the survival of cancer patients. By reducing cell death, particularly cellular apoptosis, the tumor loses its drive for proliferation and metastasis. Logically, even if it cannot lead to a cure, it should be able to slow down cancer progression and confer a survival benefit to patients. Interestingly, this is not just theoretical; there are cases that exemplify this strategy. For instance, while anti-angiogenic medicines aim to inhibit tumor growth and metastasis by blocking continuous angiogenesis, traditional Chinese medicine employs an opposite approach by promoting blood circulation to remove blood stasis. This strategy improves the microenvironment of cancer cells, reduces cellular apoptosis, and thus slows down cancer progression and reduces metastasis. For example, Tanshinone had been shown to inhibit the metastasis of hepatocarcinoma and prolong the survival of patients [29]. In contrast, anti-angiogenic treatments often result in increased cancer metastasis [30–32]. More examples can be found in the use of immune inhibitors in cancer treatment, such as glucocorticoids and rapamycin. A notable example is interferon, a cytokine once widely used in cancer treatment due to its perceived ability to enhance immunity against cancer. However, interferon can induce the expression of p202, a protein that strongly inhibits tumor cell apoptosis and growth [33, 34]. Therefore, the therapeutic effect of interferon against cancer may be attributed to its inhibition of cellular apoptosis rather than its enhancement of immunity.

Epilogue

Assumptions and misunderstandings are inherent in scientific endeavors. While assumptions play a crucial role, misunderstandings can be challenging to circumvent. Despite the prevalence of incorrect assumptions, science thrives on continual falsification. The notion that reduced apoptosis contributes to cancer formation, along with cancer cells’ resistance to apoptosis, represents flawed assumptions and misconceptions that run counter to cancer pathology. Although this article’s perspective garners some support from literature and partial agreement among scholars, it remains a subtle voice within the cancer research community. It is our aspiration that this article will prompt more scholars to engage with and deliberate on this topic; embracing both dissent and endorsement will bolster the validation of this theoretical research, thereby propelling advancements in the field.

Funding

This study is supported by grants from Shenzhen Science and Technology Innovation Committee (JCYJ20170307143804397), and China National Natural Science Foundation Committee (82472648).

Conflicts of interest

The authors declare no conflicts of interest.

Data availability statement

This article has no associated data generated and/or analyzed.

Author contribution statement

RAW conceived the idea and wrote the paper. ZGL discussed the idea extensively, read and approved the manuscript.

Ethics approval

Ethical approval was not required.

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Cite this article as: Wang R-A & Li Z-G. Revisiting the role of cell death in cancer – promotion rather than inhibition. Visualized Cancer Medicine. 2025; 6, 7. https://doi.org/10.1051/vcm/2025006.

All Figures

thumbnail Figure 1

Apoptosis vs. pathological necrosis. This image was taken from a breast cancer case. The area to the left of the yellow line is pathologically called necrosis, while the nucleated cells indicated by the arrows are undergoing apoptosis. This illustrates that the term “necrosis” in pathology often refers to extensive cell death, which can include both apoptosis and other forms of cell death. Bar = 20 µm.
In the text
thumbnail Figure 2

Apoptosis, Bcl-2 expression, and cell proliferation. The left panel shows a case of Burkitt lymphoma, characterized by extensive apoptosis, which creates a “starry sky” appearance due to phagocytosis of cell debris by the macrophages in H.E staining. Notably, Bcl-2 is not expressed, and the tumor proliferation index is extremely high. The right panel depicts a case of low-grade follicular lymphoma (FCL), in which apoptosis is rarely observed. Bcl-2 expression is abnormally high due to its dislocation to the neighborhood of immunoglobulin heavy chain (IgH), resulting in a significantly lower tumor proliferation index. All the pictures are the same magnification. Bar = 60 µm.
In the text

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