Cancer Senescence | Ajou Translational Medicine (ATM) Lab

Cellular senescence is defined as an irreversible cell cycle arrest caused by various stresses. Interestingly, although cancer cells have the highest proliferative capacity within our body, they can also be driven into a senescent state by massive insults within the tumor microenvironment.

Senescence associated beta galactosidase staining (blue) shows senescent cancer cells in various cancer types.
Source: (Park et al., 2021)

Non-proliferating cancer cells? You might find them a bit odd, and scientists initially thought the same. Consequently, they considered the possibility that these cancer cells might be a consequence of our body’s defense mechanism against cancer progression; indeed, this is the case in the initial stages of carcinogenesis when oncogenes are highly overexpressed.

However, in 2017, our laboratory was the first to reveal that these senescent cancer cells actually possess cancer-promoting potency. In cases of papillary thyroid cancer, we found that senescent cancer cells are located at the invasive front of the cancer tissue and actually act as the spearhead of cancer invasion.

Senescent thyroid cancer cells (blue) are at the spearhead of the invasion (left). A schematic image is shown on the right.
Source: Kim Y.H. et al. Nat. Commun. (2017)

Moreover, senescent cancer cells are closely associated with the immune microenvironment of cancer. Cytotoxic T cells are one of the few cell types that have the potency to kill cancer cells. Indeed, senescent cancer cells express specific proteins that inhibit the infiltration of cytotoxic T cells into the cancer tissues. In other words, the presence of senescent cancer cells hinders and weakens the cancer-killing potency of our normal immune system.

Senescent cancer cells (p16^INK4A-positive cancer cells) and CD8⁺ cytotoxic T cells are shown (left). The underlying mechanism by which senescent cancer cells inhibit the infiltration of cytotoxic T cells (right). Source: Choi Y.W. et al. Adv. Sci. (2021)

Another notable feature is the uneven distribution of senescent cancer cells within cancer tissues. Interestingly, senescent cancer cells are located at the invasive front, while non-senescent, proliferating cancer cells are found near the relative center. In a subsequent study, we discovered that senescent tumor cells evolve from non-senescent tumor cells at the center. These senescent cancer cells, an evolved form of cancer cells, express various cancer-promoting factors, such as collagen and elastin-degrading molecules, and promote local invasion and metastasis.

The distribution of p16^INK4A-positive senescent cancer cells (upper). Cellular senescence and cancer cell evolution (lower).
Source: (Park et al., 2024)

Although various interesting studies have been performed on senescent cancer cells, many questions remain unanswered. How do senescent cancer cells evade immune attacks and survive? How are they associated with cancer cell survival after chemotherapy? How are senescent cancer cells related to the long-term relapse of cancer? If you are interested in exploring these fascinating questions, please contact us to join or collaborate with our team!

References

2024

Cell Rep.

(1st author) Cellular senescence is associated with the spatial evolution toward a higher metastatic phenotype in colorectal cancer

Soon Sang Park, Young-Kyoung Lee, Yong Won Choi, and 8 more authors

Cell Reports, 2024

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In this study, we explore the dynamic process of colorectal cancer progression, emphasizing the evolution toward a more metastatic phenotype. The term “evolution” as used in this study specifically denotes the phenotypic transition toward a higher metastatic potency from well-formed glandular structures to collective invasion, ultimately resulting in the development of cancer cell buddings at the invasive front. Our findings highlight the spatial correlation of this evolution with tumor cell senescence, revealing distinct types of senescent tumor cells (types I and II) that play different roles in the overall cancer progression. Type I senescent tumor cells (p16INK4A+/CXCL12+/LAMC2−/ MMP7−) are identified in the collective invasion region, whereas type II senescent tumor cells (p16INK4A+/CXCL12+/LAMC2+/MMP7+), representing the final evolved form, are prominently located in the partial-EMT region. Importantly, type II senescent tumor cells associate with local invasion and lymph node metastasis in colorectal cancer, potentially affecting patient prognosis.

2021

Exp. Mol. Med.

(1st author) Senescent tumor cells: an overlooked adversary in the battle against cancer

Soon Sang Park, Yong Won Choi, Jang-Hee Kim, and 2 more authors

Experimental & Molecular Medicine, 2021

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Senescent cells in cancer tissue, including senescent fibroblasts and macrophages, have been reported to increase the malignant potency of cancer cells by secreting senescence-associated secretory phenotype (SASP). Otherwise, Senescence of tumor cells has been believed to inhibit tumor growth by halting the massive proliferation and increasing the chances of immune clearance. In particular, senescent tumor cells (STCs) have been thought that they rarely exist in carcinomas because oncogene-induced senescence needs to be overcome for protumorigenic cells to become malignant. However, recent studies have revealed that a considerable number of STCs are present in cancer tissue, even in metastatic sites. In fact, STCs are widely involved in cancer progression by leading to collective invasion and building a cytokine barrier to protect nonsenescent tumor cells from immune attack. Furthermore, therapy-induced STCs can induce tumor progression and recurrence by increasing stemness. However, obscure causative factors and their heterogeneity in various cancers make it difficult to establish the physiological role of STCs. Here, we summarize and review the current knowledge of the pathophysiology and role of STCs. We also outline the current status of therapeutic strategies for directly removing STCs or modulating the SASPs to maximize the positive functions of STCs while suppressing the negative functions.