Recent studies reveal that pancreatic tumors do not function in isolation. Instead, they modify adjacent healthy tissues, effectively reprogramming them to facilitate cancer invasion. This discovery sheds light on the challenges of managing pancreatic cancer once it begins to metastasize.
A Challenging Cancer with Serious Consequences
The predominant type of pancreatic cancer is adenocarcinoma, originating in the glandular cells responsible for producing pancreatic juice. This variant constitutes approximately 90% of all pancreatic cancer cases. Although pancreatic cancer is not among the most commonly diagnosed cancers, it is recognized for its aggressive nature, with its mortality rate nearly paralleling its incidence rate.
Globally, around 510,000 new cases of pancreatic cancer are diagnosed each year, with a similar number of fatalities reported annually.
In Brazil, the National Cancer Institute (INCA) estimates indicate approximately 11,000 new cases and 13,000 deaths each year. "It's a highly aggressive cancer that poses significant treatment challenges. Only about 10% of patients can expect long-term survival, such as five years post-diagnosis," explains Pedro Luiz Serrano Uson Junior, an oncologist and co-author of the study.
The Importance of Nerve Invasion
One critical factor contributing to the perilous nature of pancreatic cancer is a phenomenon known as perineural invasion. This occurs when cancer cells infiltrate and spread along nerves, leading to intense pain and enabling the tumor to reach distant body parts more readily. "Perineural invasion serves as an indicator of cancer aggressiveness," Uson elaborates.
As nerves connect various body regions, cancer cells that infiltrate these pathways acquire new routes for dissemination.
Charting the Tumor's Hidden Support System
This research was conducted at the Center for Research on Inflammatory Diseases (CRID), part of FAPESP's Research, Innovation, and Dissemination Centers (RIDCs). The study was spearheaded by researcher Carlos Alberto de Carvalho Fraga, with Helder Nakaya as the principal investigator. Nakaya also serves as a senior researcher at Einstein Israelite Hospital and is a professor at the University of São Paulo's School of Pharmaceutical Sciences.
To investigate the mechanisms of nerve invasion, the team utilized advanced tools that analyze the activity of thousands of genes in individual cells while precisely mapping their locations within tumor tissue. "We successfully integrated data from numerous samples with remarkable resolution," Nakaya remarks.
Upon examining 24 pancreatic cancer samples, the researchers discovered that the stroma, the connective tissue supporting the tumor, actively contributes to cancer progression rather than merely acting as a passive structure.
The Role of Periostin and Tissue Remodeling
One of the most significant findings of the study involved pancreatic and stellate cells that produce substantial amounts of periostin. This protein is recognized for its ability to remodel the extracellular matrix, the framework that organizes and sustains healthy tissue.
Tumor cells depend on significant alterations to this matrix to penetrate tissue and access nearby nerves. This remodeling process involves specialized enzymes and extensive tissue disruption. "Periostin plays a crucial role in this remodeling, facilitating tumor cell invasion," Nakaya explains. Once cancer cells reach a nerve, it can act as a "pathway" that aids their further spread.
Challenges in Treatment Accessibility
As the tumor environment evolves, it triggers a desmoplastic reaction, characterized by the accumulation of dense, fibrous tissue around the tumor, composed of cells and proteins that stiffen and inflame the area. This hardened tissue hinders the penetration of chemotherapy and immunotherapy drugs into the tumor.
This protective microenvironment allows cancer cells to thrive and continue their spread. "That's why pancreatic cancer remains exceptionally challenging to treat," Uson states.
Early Spread Leads to Dismal Prognosis
According to Uson, the tumor's capacity to invade surrounding tissues significantly contributes to the poor prognosis many patients face. "Perineural invasion indicates that cancer cells have gained mobility. They escape the tumor mass, traverse healthy tissue, and reach nerve and lymphatic bundles, which transport them to other body regions, facilitating metastasis."
More than half of pancreatic cancer cases exhibit signs of perineural invasion at an early stage, yet this spread is typically identified only post-surgery. "Regrettably, we often discover this perineural invasion after it has already occurred, usually evident only in the surgical specimen sent for biopsy," Uson notes.
A Promising Target
Given these hurdles, the researchers propose that periostin could serve as a promising target for future therapies. Reducing its activity or eliminating the stellate cells responsible for its production may help curtail nerve invasion and slow the cancer's spread. "This research highlights pathways that could inform future strategies for treating pancreatic cancer," Nakaya emphasizes.
Clinical trials in other cancer types are already testing antibodies designed to inhibit periostin. Nakaya believes these efforts could reveal whether similar strategies might be effective in pancreatic cancer.
Uson points out that this approach aligns with the broader trend toward precision medicine. "If we can develop antibodies or drugs that inhibit these stellate cells, we will have tools to prevent the tumor from acquiring invasive capabilities at an early stage." He adds that, as of now, no treatment specifically targets perineural invasion, and such therapies could also benefit patients with other cancers, including those of the intestine and breast.
Beyond identifying new therapeutic targets, the study underscores the potential of advanced data analysis utilizing public databases. "We were able to pose and address new questions that the original authors had not considered," Nakaya states.
The researchers assert that the next step involves translating these insights into treatments that act before invasion occurs. "Precision medicine is progressing. In the future, we will treat patients based on genomic and molecular alterations rather than solely on tumor type. This represents a significant advancement in oncology," concludes Uson.