When we think of cancer, we often imagine a mass of cells growing uncontrollably. But what many don’t realize is that beyond its shape or size, what makes cancer truly complex is its behavior. Cancer is a disease that acquires biological “skills” to survive, resist therapies, spread, and evade the immune system. Understanding those skills isn’t easy, especially since, until recently, we could only study them through invasive biopsies or limited lab analyses. However, an advanced medical technology is beginning to change that story: molecular positron emission tomography, better known as molecular PET.
In their article published in Cancer (2022), researchers Chentao Jin, Xiaoyun Luo, Xiaoyi Li, Rui Zhou, Yan Zhong, Zhoujiao Xu, Chunyi Cui, Xiaoqing Xing, Hong Zhang, and Mei Tian present a comprehensive review of how PET can help us “see” cancer in action inside the human body—without having to extract tissue. This type of imaging detects cellular and molecular processes using small radioactive molecules called radiopharmaceuticals, which bind to specific structures on the tumor. Rather than simply observing a mass or lump, PET reveals how that lump behaves: whether it’s growing, dying, evading the immune system, or changing its form, among other aspects.
What’s most interesting about the authors’ approach is that they organize this information using the well-known framework of the “hallmarks of cancer,” a concept developed by Hanahan and Weinberg that groups the main biological characteristics that cancer cells acquire to survive and spread. Jin and his colleagues aim to show how molecular PET can capture, in real time and within the body, many of those traits. In other words, not just seeing cancer, but understanding its unique personality in each patient.
One of the most representative hallmarks of cancer is its ability to multiply without control. To do this, tumor cells activate specific receptors like EGFR (epidermal growth factor receptor) or estrogen receptors. These receptors can be visualized using PET with radiolabeled antibodies such as 89Zr-cetuximab for EGFR or 18F-fluoroestradiol for estrogen receptors. This information is crucial because it allows clinicians to anticipate whether a patient will respond to targeted therapies. However, even in patients with high EGFR expression, treatment response can vary due to mutations in other cellular components. Hence, the importance of observing the entire molecular environment, not just a single marker.
Another aspect explored in depth by Jin and his team is how cancer avoids programmed cell death, also known as apoptosis. Under normal conditions, damaged cells self-destruct, but cancer develops mechanisms to escape that fate. Using tracers that detect key proteins in this process, such as caspases, PET can evaluate whether a therapy is successfully triggering cell death in the tumor. Even more refined techniques have been developed, like reporter genes that activate only when a cell enters apoptosis, providing clearer and more specific signals.
Similarly, cancer also perpetuates itself over time thanks to its ability to become “immortal.” Normally, cells have a limited number of divisions before they die, but cancer cells activate an enzyme called telomerase, which allows them to keep dividing indefinitely. Thanks to PET, it is now possible to visualize this activity using tracers targeting the genetic components of telomerase, opening new possibilities for therapies that aim to block this process.
Furthermore, cancer needs to nourish its growth, and to do so, it stimulates the formation of new blood vessels—a process known as angiogenesis. The authors explain that PET can detect proteins like VEGF (vascular endothelial growth factor), responsible for this vascular proliferation, or indirectly measure the tumor’s oxygenation status, since more hypoxic tumors tend to form more vessels. This type of information helps determine whether a patient might benefit from anti-angiogenic drugs.
Jin et al. also explore how PET can visualize processes that facilitate metastasis, such as epithelial-mesenchymal transition (EMT) or the presence of cancer stem cells (CSCs), which have the capacity to initiate new tumors in distant organs. Although it’s still an evolving field, tracers already exist that can identify these dangerous cells—something that could be vital in preventing recurrence.
The article also dedicates a section to another critical aspect: genomic instability. Cancer accumulates mutations over time, many of which make it more aggressive. Using tracers that detect DNA damage or specific gene mutations, PET can show how “unstable” a tumor is, which has both prognostic and therapeutic implications. For example, if a tumor shows high DNA repair activity, it may be resistant to certain treatments but vulnerable to others, such as PARP inhibitors.
The immune system also plays a central role. Many tumors hide from our defenses or even manipulate them to avoid attack. Thanks to PET, it is now possible to see T-cell infiltration within tumors or the expression of immunosuppressive proteins like PD-L1. This information is essential in the age of immunotherapy, as it helps identify patients who are most likely to benefit from this type of treatment.
A particularly interesting finding mentioned by the authors is that when using 18F-FDG (the most commonly used radiotracer for visualizing glucose consumption), it was observed that it is not always the tumor cells that consume the most glucose, but rather the immune cells surrounding them. This could explain why some tumors appear very active in PET scans but don’t respond to treatment: the signal is coming from the body’s defenses, not the tumor itself.
Figure 1. Representation of how positron emission tomography (PET) enables the visualization of key biological features of cancer, known as hallmarks. Each panel illustrates a specific tumor trait along with the corresponding PET molecular imaging tool, including radiolabeled antibodies, glucose analogs, or reporter genes. These technologies allow real-time assessment of processes such as uncontrolled proliferation, immune evasion, genomic instability, altered metabolism, and tumor microenvironment remodeling, facilitating more accurate in vivo cancer phenotyping.
Finally, the article emphasizes that although the potential of PET is enormous, there is still much to develop. There are markers that still cannot be visualized, processes not yet fully understood, and technologies that need refinement. Moreover, for these images to be used routinely, they must undergo rigorous clinical validation, demonstrate cost-effectiveness, and be standardized internationally.
In conclusion, the work by Jin and his colleagues presents an ambitious yet well-founded vision of the future of cancer diagnosis and monitoring. Positron emission tomography is no longer just a tool to see if a tumor is present—it’s a method to understand how cancer thinks, acts, and evolves inside the human body. Integrating this technology with molecular biology, artificial intelligence, and personalized medicine could completely revolutionize how we approach this disease. What was once only visible under the microscope can now be seen in real time inside the body. And that, without a doubt, changes the rules of the game.
Main Reference:
Jin, C., Luo, X., Li, X., Zhou, R., Zhong, Y., Xu, Z., Cui, C., Xing, X., Zhang, H., & Tian, M. (2022). Positron emission tomography molecular imaging-based cancer phenotyping. Cancer, 128(14), 2704–2716. https://doi.org/10.1002/cncr.34228
Other References:
Soerjomataram, I., & Bray, F. (2021). Planning for tomorrow: global cancer incidence and the role of prevention 2020-2070. Nature reviews. Clinical oncology, 18(10), 663–672. https://doi.org/10.1038/s41571-021-00514-z
McGranahan, N., & Swanton, C. (2017). Clonal Heterogeneity and Tumor Evolution: Past, Present, and the Future. Cell, 168(4), 613–628. https://doi.org/10.1016/j.cell.2017.01.018
Gambhir S. S. (2002). Molecular imaging of cancer with positron emission tomography. Nature reviews. Cancer, 2(9), 683–693. https://doi.org/10.1038/nrc882
