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Nayela Chowdhury
Pancreatic ductal adenocarcinoma (PDAC) is an exocrine tumor of the pancreas and constitutes up to 95% of all pancreatic cancer cases. PDAC exhibits one of the poorest prognosis of all solid cancers and is associated with a very low overall and progression-free survival rate. Even though many molecular pathways underlying PDAC have been extensively studied, successful translation of these findings to the clinic has remained elusive. One hypothesis for the difficulty in treating PDAC has revolved around the role of the PDAC tumor microenvironment, which has been implicated in tumor-protective roles such as drug resistance, tumor proliferation and spread. The PDAC stroma thrives on a complex interplay of fibroblasts, myofibroblasts, immune cells, endothelial cells, extracellular matrix (ECM), cytokines and growth factors, creating a tumor microenvironment which is very fibrous and contributes to the aggressive nature of the disease [1, 2]. Fibroblasts are typically responsible for maintaining tissue structure but can transform into cancer-associated fibroblasts (CAFs) in response to signals from cancer cells or alterations in the tumor microenvironment. A significant portion, around 80-90%, of PDAC tumors are made up of CAFs which play a role in remodeling the tissue and contributing to the progression of the disease, although the exact mechanisms are still being studied [3].
In recent years, our understanding of CAFs has substantially increased by the development of single-cell transcriptomic and proteomic technologies which are used to study specific cell types within the tumor microenvironment, aiding in the development of targeted therapies. This has revealed the complex heterogeneity and interplay of several different subpopulations of CAFs that can either promote or suppress the tumor [4-6]. The most common CAF subtypes that are widely recognized in PDAC are myofibroblast CAF (myCAF), inflammatory CAF (iCAF) and antigen presenting CAFs (AP CAFs). Some subtypes are inconvertible and are able to transition or change into other CAF types, adapting to different roles or functions as needed, while others are more specialized and remain committed to specific roles or functions associated with their distinct lineage.
Dual Roles of CAFs: A Complex Dichotomy
CAFs are universally recognized as important players in the tumor’s capacity to self-renew, differentiate, and metastasize through the secretion of inflammatory cytokines, growth factors and cellular vesicles. These cells are believed to play a crucial role in tumor initiation, growth, progression, and recurrence. In PDAC, it has been shown that CAFs aid in tumor survival [7]. CAFs can modify the tumor microenvironment in PDAC, making the tumor microenvironment more favorable for epithelial-to-mesenchymal transition and subsequent metastasis [8]. Epithelial-Mesenchymal Transition is a process where cells lose their typical epithelial characteristics and acquire properties of mesenchymal cells, promoting cell migration and invasion during cancer metastasis.
Desmoplasia is the growth of abnormal and dense connective tissue in response to tumor growth or inflammation. It often creates a tough, fibrous environment around the tumor. CAFs cause desmoplasia which can affect the success of surgery to excise pancreatic tumors and serve as a barrier to delivery of chemotherapeutic drugs. CAFs exposed to chemotherapy have been shown to mediate exosome-mediated survival and proliferation of pancreatic cancer and associated drug resistance via several miRNAs and proteins [9, 10]. They are known to create a drug delivery barrier and impede efficient drug delivery during chemotherapy. Resistance to gemcitabine, one of the most widely used drugs in the treatment of PDAC, has also been linked to CAFs through mediation of epithelial to mesenchymal transition [11]. This can potentially affect treatment outcomes in patients.
Several reports have concluded that myofibroblasts expressing a protein called α-smooth muscle actin (αSMA) play tumor suppressive roles, and depletion of this subtype is detrimental to patient survival. Studies with depletion of CAFs in the tumor microenvironment have also been associated with an invasive phenotype of pancreatic cancer and immunosuppression accompanied by reduced survival in mice [12, 13]. In genetically engineered mouse models of PDAC, myofibroblast depletion on fibroblasts resulted in significantly more invasive tumors compared to control. Similarly, decreased stromal αSMA positive myofibroblast depletion also resulted in more aggressive tumors [14], suggesting a protective role of the microenvironment and requiring strategies targeting CAFs to be approached with caution.
The role of CAFs in PDAC is still actively widely investigated. The pancreatic tumor stroma is a dynamic and integral component of pancreatic cancer pathophysiology, with CAFs playing a pivotal role in this microenvironment. A comprehensive understanding of CAF biology is fundamental for achieving future breakthroughs in utilizing CAFs for therapeutic purposes, not only in PDAC but across various cancer types. By delving deeper into the heterogeneity of CAF behavior, researchers and clinicians can identify novel avenues for therapeutic intervention. These may include strategies to modulate CAF activity, disrupt their interactions with tumor cells, or harness their functions to prevent metastatic spread of PDAC or enhance the efficacy of conventional treatments. Moreover, understanding the intricacies of CAF populations and their evolving roles within the tumor microenvironment is essential for tailoring personalized treatment approaches, ultimately improving patient outcomes. Unraveling the complexities of CAF biology within the pancreatic tumor stroma holds great promise for revolutionizing cancer therapy, particularly in the context of PDAC.
Edited by Muhammad Ayhan Murtaza
Article Figure: Key components of Pancreatic Ductal Adenocarcinoma (PDAC) and its tumor microenvironment: tumor cells, desmoplastic stroma (fibroblasts, myofibroblasts, extracellular matrix), immune cells and endothelial cells. The PDAC TMA is marked by fibrous stroma and critical interactions within the tumor microenvironment which influences tumor behavior. Developed with Biorender.
Works Discussed
1. Li, K.-Y., et al., Pancreatic ductal adenocarcinoma immune microenvironment and immunotherapy prospects. Chronic diseases and translational medicine, 2020. 6(1): p. 6-17.
2. Parente, P., et al., Crosstalk between the tumor microenvironment and immune system in pancreatic ductal adenocarcinoma: potential targets for new therapeutic approaches. Gastroenterology research and practice, 2018. 2018.
3. Sun, Q., et al., The impact of cancer-associated fibroblasts on major hallmarks of pancreatic cancer. Theranostics, 2018. 8(18): p. 5072.
4. Chang, H.Y., et al., Gene expression signature of fibroblast serum response predicts human cancer progression: similarities between tumors and wounds. PLoS Biol, 2004. 2(2): p. e7.
5. Chang, H.Y., et al., Diversity, topographic differentiation, and positional memory in human fibroblasts. Proceedings of the National Academy of Sciences, 2002. 99(20): p. 12877-12882.
6. Jiang, H., et al., Pancreatic ductal adenocarcinoma progression is restrained by stromal matrix. The Journal of clinical investigation, 2020. 130(9): p. 4704-4709.
7. Nallasamy, P., et al., Pancreatic tumor microenvironment factor promotes cancer stemness via SPP1–CD44 Axis. Gastroenterology, 2021. 161(6): p. 1998-2013. e7.
8. Ligorio, M., et al., Stromal microenvironment shapes the intratumoral architecture of pancreatic cancer. Cell, 2019. 178(1): p. 160-175. e27.
9. Richards, K.E., et al., Cancer-associated fibroblast exosomes regulate survival and proliferation of pancreatic cancer cells. Oncogene, 2017. 36(13): p. 1770-1778.
10. Zhang, L., et al., Micro-RNA-21 regulates cancer-associated fibroblast-mediated drug resistance in pancreatic cancer. Oncology research, 2018. 26(6): p. 827.
11. Feldmann, K., et al., Mesenchymal plasticity regulated by Prrx1 drives aggressive pancreatic cancer biology. Gastroenterology, 2021. 160(1): p. 346-361. e24.
12. Amakye, D., Z. Jagani, and M. Dorsch, Unraveling the therapeutic potential of the Hedgehog pathway in cancer. Nature medicine, 2013. 19(11): p. 1410.
13. Özdemir, B.C., et al., Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival. Cancer cell, 2014. 25(6): p. 719-734.
14. Rhim, A.D., et al., Stromal elements act to restrain, rather than support, pancreatic ductal adenocarcinoma. Cancer cell, 2014. 25(6): p. 735-747.
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