Tumor stroma conforms the structural components which hold tumor components together [1]. In general, stromal fibrosis is viewed as a histopathological finding appearing in most tumors. As such, pancreatic fibrosis is a frequent condition that develops in pancreatitis and cancer [2]. It can be initiated from changes in the physiology of cells that, under healthy conditions, contribute to the homeostasis and to the maintenance of the stroma under control in the gland. Abnormal activation of cells by signals from different origin leads them to active proliferation. As a consequence, deposition of extracellular matrix components takes place. The appearing environment will have consequences that may vary depending on the extent of the fibrosis. Excessive development of fibrotic tissue, in turn, can impair the functions of pancreas [3]. An unexpected outcome is the facilitation of the development of inflammatory or cancerous cells within the gland.

Pancreatic cancer is the 4th leading cause of cancer deaths [4] and has an overall 5-year survival of 7–9% [5]. Moreover, pancreatic cancer is projected to emerge as the second leading cause of cancer-related death after 2030 with limited therapeutic options and still short-term survival [6]. The poor survival is due in part to a lack of effective therapies, majorly related with the role of stroma and its contribution to the growth of the tumor tissue.

Along the past years, and especially at present, deep attention has been paid to the identification of regulators of the stroma in cancer disease, including pancreatic cancer. Nowadays, it is accepted that a heterogeneous population of cells contribute to stroma formation, which include fibroblasts, pancreatic stellate cells (PSC), and a large number of cells of the immune system [7]. Interestingly, a vivid interrelationship is established among them within the growing mass, which allows the tumor tissue to expand and its cells to migrate and to settle down beyond the tumor environment, leading to metastasis [8]. Thus, it is important to understand the cellular and molecular basis of the stroma and to unravel the mechanisms for cell-to-cell communication to gain a better knowledge of pancreatic disease development and to find a potential cure.

In their contribution, Brumskill et al. provide evidences for the role of cancer-associated fibroblasts (CAFs) to the impact the efficacy of chemotherapy drugs used in the clinic. Different pancreatic cancer cell types were used in their study, MIAPaCa-2, PANC-1, Suit-2, BxPC-3, and AsPC-1, which were co-cultured with CAFs. Gemcitabine and paclitaxel were able to diminish the viability of pancreatic cell lines but not that of CAFs, either in 2D or 3D cultures. Moreover, CAFs diminished the anti-proliferative effect of chemotherapy drugs. A major conclusion of their study raises questions, one of which involves the potential contribution of non-cancer cells of the tumor microenvironment (TME) to treatment response. As such, the TME in pancreatic ductal adenocarcinoma (PDAC) exhibits dynamics in its response to chemotherapeutic agents, and CAFs play a much more elaborate role in chemotherapeutic resistance than just providing a physical barrier.

Muñoz Velasco et al. provides a comprehensive review about the chemoresistance and the large tumor stroma that occupies most of the tumor mass. Major attention is paid to the fact that immune cells included in the tumor mass release inflammatory cytokines and can generate an immunosuppressive environment, liable for the growth of a tumor. Moreover, evidence is added for the role of CAFs to provide a protective coverage that would difficult the access of chemotherapy to the tumor. Therefore, targeting the immunosuppressive features in TME is a promising approach among the many ways explored for the treatment of PDAC. Information about different therapies that are being studied to counteract the tumor is summarized.

On their turn, Barrera et al. highlight the critical role of microRNAs (miRNAs), small non-coding RNAs, in tumor development, and resistance to chemotherapy. A major role played by extracellular vesicles is critical for the transfer of information and signaling molecules, including miRNAs, between cells. The role of the cargo in the differentiation of normal fibroblasts into CAFs and their contribution to the development of PDAC and metastasis is reviewed. Further discussion on the role of miRNAs in the responses to therapy is provided.

Within the TME, a bidirectional communication is established between the tumor cells, the cells forming the stroma, and the healthy cells present in the neighborhood. The complex interrelationship will direct each cell’s fate. Among the major mechanisms available for cell communication, the extracellular vesicles have gained attention. Therefore, intense research is being carried out nowadays on their role in cell communication in cancer. Dr. Daniel Closa’s contribution contains relevant information about extracellular vesicles’ means of transfer of resistance to chemotherapeutic drugs, promotion of epithelial-mesothelium transition, modification of the phenotype of macrophages, or the induction of the expression of molecules that alter the extracellular matrix to facilitate migration and metastasis. Additionally, modifications of their structure and content could be used as first-rate therapeutic targets, in order to enhance the effectiveness of treatments against PDAC.

With regard to targeting of stroma, Liu et al. have prepared a manuscript in which it is highlighted that methods which combine stroma-targeting with anti-cancer therapy may be a viable alternative for increasing drug penetration. Indispensable components of the stroma are blood vessels, which must necessarily be taken in to account, because they represent channels for nutrients supply to the tumor. An overview of the current understanding of the three principal constituents of the PDAC stroma and new promising therapeutic targets is provided. Importantly, the authors refer to the fact that, given that CAFs exhibit acute dynamic plasticity, shifting the ratio of specific CAF sub-populations at certain timepoints, rather than ablation, might be a more suitable approach to control tumorigenesis and metastasis.

Finally, Estaras et al. provide evidence for putative anti-proliferative actions of melatonin on PSC. Melatonin (N-acetyl-5-methoxytryptamine) is produced in the mammalian pineal gland and released into the blood during the night, following a circadian rhythm. Melatonin receptors are widely distributed in the body, which supports that the indoleamine is able to regulate a wide array of physiological processes, including pancreatic function. Moreover, the indoleamine is also produced extrapenially and, in addition, can be found in vegetables and fruits [9, 10]. The potential role of melatonin as cellular protector and anti-cancer agent has been highlighted [11]. In this line, melatonin arises as a resident ally against disease [12]. The work by Estaras et al. provides interesting evidence for the regulation of cell proliferation by melatonin. The indoleamine modulates mitochondrial physiology and energy metabolism as sources of energy to be used in major pathways involved in the proliferation of PSC. In spite of causing massive cell death, melatonin diminishes cell proliferation, therefore, collaborating in an anti-proliferative status within the stroma. Indeed, the results shown are in the line suggested by Liu et al. who, as mentioned above, suggest that modulation of the ratio of specific subpopulations at certain timepoints, rather than their elimination, could represent a valuable tool to control tumorigenesis.

We sincerely hope that this issue provides the reader with interesting findings on the role of the stroma in the pathophysiology of the pancreas, especially in terms on how new studies could be designed to approach the prophylaxis and/or therapy of pancreatic cancer.

We are grateful to Dr. MP Lostao and Dr. MJ Moreno-Aliaga, editors in chief of the Journal of Physiology and Biochemistry, for their support, advice, and invaluable help making this Special Issue possible. Finally, thanks to all authors who contributed with their work to be included in this Issue.