Cancer treatment is rarely a simple intervention. Each therapy applied to a tumor triggers a cascade of biological responses that affect not only malignant cells, but also blood vessels, the immune system, and the surrounding tissues.
In recent years, research has begun to reveal that some of these responses, although unintended, can influence the cancer’s ability to spread to other organs.
One of the greatest challenges in oncology remains metastasis, which is responsible for the majority of cancer-related deaths. For a tumor cell to form a metastasis, it must complete a series of highly complex steps: detach from the primary tumor, cross the wall of a blood vessel, survive in circulation, exit into a distant organ, and finally adapt to a new environment.
For a long time, these events were assumed to depend almost exclusively on genetic mutations within the tumor cell. However, it is now known that the environment surrounding the tumor plays an equally decisive role.
Within this environment, known as the tumor microenvironment, there are specialized microscopic structures that facilitate the entry of cancer cells into the bloodstream.
These structures, called TMEMs (tumor microenvironments of metastasis), form when a highly invasive tumor cell comes into direct contact with a blood vessel endothelial cell and a specific macrophage.
This point of contact acts as a kind of temporary “door” through which tumor cells can escape into the circulation.
Recent research has shown that certain chemotherapy regimens can increase the number of TMEM sites within tumors. This phenomenon is not due to accelerated tumor growth, but rather to the changes these treatments induce in the tumor microenvironment at both the cellular and molecular levels.
In particular, an increase has been observed in tumor-associated macrophages—immune system cells that, instead of exerting a defensive function, can promote tumor invasion by altering the structure and permeability of blood vessels.
Macrophages are highly versatile cells whose function depends on the context in which they operate. While they often play a protective role during infections, in cancer some macrophages adopt characteristics that promote tumor progression, stimulate new blood vessel formation, and facilitate cellular dissemination.
Chemotherapy, by causing damage to tumor tissue, triggers an inflammatory response that attracts these immune cells. Paradoxically, this reaction can generate a transient environment that favors the escape of resistant tumor cells into the circulation.
Another key component in this process is the expression of proteins involved in cellular motility. Among them is Mena, a protein that controls the reorganization of the actin cytoskeleton and enables cells to adopt the dynamic shapes required for movement.
Specific variants of Mena are closely associated with highly invasive behavior, and it is precisely tumor cells expressing these variants that are most frequently found at TMEM sites.
After certain chemotherapy treatments, an increase has been detected in the relative proportion of tumor cells expressing these invasive forms of Mena.
This does not imply that chemotherapy creates new malignant cells, but rather that it may exert selective pressure favoring the survival of cells with greater plasticity and migratory capacity.
In this scenario, while most of the tumor is eliminated, a subgroup of cells with high invasive potential manages to persist and take advantage of a microenvironment that temporarily becomes more permissive to dissemination.
These findings come primarily from studies in animal models and from analyses of tumor biopsies from patients, particularly in breast cancer. In these studies, researchers observed that shortly after chemotherapy, TMEM density and tumor cell intravasation—that is, entry into blood vessels—increased. Over time, these changes tended to decrease, suggesting that the effect is transient, but potentially relevant.
It is essential to interpret these results with caution. Chemotherapy remains one of the most effective treatments for reducing tumor size, alleviating symptoms, and prolonging survival in millions of patients. Its clinical benefits are well established.
However, these studies highlight that the impact of a therapy is not limited to its direct effect on cancer cells, but also includes profound modifications to the biological environment in which the tumor exists.
Far from discrediting chemotherapy, this line of research opens the door to more refined therapeutic strategies. For example, combining chemotherapy with treatments that block TMEM formation, inhibit pro-tumor macrophages, or strengthen antitumor immune responses could reduce the risk of dissemination without compromising the effectiveness of the primary treatment.
In addition, the identification of TMEMs and proteins such as Mena as biological markers offers new opportunities for personalized medicine.
Measuring TMEM density in a tumor or assessing the expression of invasive Mena variants could help predict metastatic risk or guide decisions about which therapeutic combinations are most appropriate for each patient.
Figure 1. Systemic chemotherapy can reshape the tumor microenvironment beyond its direct cytotoxic effects. By triggering inflammatory responses and recruiting specific immune cell populations, treatment may transiently increase vascular permeability at specialized tumor–vessel interfaces (TMEM), creating conditions that facilitate tumor cell intravasation and dissemination.
In this context, studies analyzing the unintended effects of chemotherapy do not represent an alarmist warning, but rather a scientific opportunity. Understanding these mechanisms allows existing treatments to be optimized and new strategies to be developed that reduce the risk of metastasis—the main obstacle to curing cancer.
Based on these findings, researchers explored whether it was possible to block this unwanted effect without interfering with the effectiveness of chemotherapy.
To do so, they evaluated an experimental drug known as rebastinib, an inhibitor of the Tie2 signaling pathway, which is a key regulator of TMEM-associated macrophage function. This drug acts specifically on pro-metastatic macrophages, reducing their ability to interact with tumor cells and blood vessels.
In the models studied, administration of rebastinib together with chemotherapy significantly reduced TMEM formation and tumor cell entry into the bloodstream, without compromising the antitumor effect of the primary treatment.
These discoveries also reinforce a central idea in modern oncology: cancer is not only a disease of tumor cells, but of the entire tissue that surrounds them. Blood vessels, immune cells, and inflammatory signals actively participate in disease progression and treatment response.
Ignoring these interactions can limit therapeutic effectiveness, whereas understanding them can transform how treatments are designed.
As research advances, it is becoming increasingly clear that the future of cancer treatment will depend on integrated approaches.
Rather than targeting a single component of the tumor, the most effective therapies will be those capable of eliminating malignant cells, modulating the immune system, and controlling the tumor microenvironment simultaneously.
Main reference:
Karagiannis, G. S., Pastoriza, J. M., Wang, Y., Harney, A. S., Entenberg, D., Pignatelli, J., Sharma, V. P., Xue, E. A., Cheng, E., D’Alfonso, T. M., Jones, J. G., Anampa, J., Rohan, T. E., Sparano, J. A., Condeelis, J. S., & Oktay, M. H. (2017). Neoadjuvant chemotherapy induces breast cancer metastasis through a TMEM-mediated mechanism. Science translational medicine, 9(397), eaan0026. https://doi.org/10.1126/scitranslmed.aan0026
Other references:
Harney, A. S., Arwert, E. N., Entenberg, D., Wang, Y., Guo, P., Qian, B. Z., Oktay, M. H., Pollard, J. W., Jones, J. G., & Condeelis, J. S. (2015). Real-Time Imaging Reveals Local, Transient Vascular Permeability, and Tumor Cell Intravasation Stimulated by TIE2hi Macrophage-Derived VEGFA. Cancer discovery, 5(9), 932–943. https://doi.org/10.1158/2159-8290.CD-15-0012
Robinson, B. D., Sica, G. L., Liu, Y. F., Rohan, T. E., Gertler, F. B., Condeelis, J. S., & Jones, J. G. (2009). Tumor microenvironment of metastasis in human breast carcinoma: a potential prognostic marker linked to hematogenous dissemination. Clinical cancer research : an official journal of the American Association for Cancer Research, 15(7), 2433–2441. https://doi.org/10.1158/1078-0432.CCR-08-2179
Oktay, M. H., Gertler, F. B., Liu, Y. F., Rohan, T. E., Condeelis, J. S., & Jones, J. G. (2012). Correlated immunohistochemical and cytological assays for the prediction of hematogenous dissemination of breast cancer. The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society, 60(3), 168–173. https://doi.org/10.1369/0022155411435153
