PLGA-based nanoparticles: An overview of biomedical applications

Cancer is associated with fibroblasts at all stages of disease progression. This Review discusses the pleiotropic actions of cancer-associated fibroblasts (CAFs) on tumour cells and postulates that they are likely to be a heterogeneous and plastic population of cells in the tumour microenvironment. Among all cells, fibroblasts could be considered the cockroaches of the human body. They survive severe stress that is usually lethal to all other cells, and they are the only normal cell type that can be live-cultured from post-mortem and decaying tissue. Their resilient adaptation may reside in their intrinsic survival programmes and cellular plasticity. Cancer is associated with fibroblasts at all stages of disease progression, including metastasis, and they are a considerable component of the general host response to tissue damage caused by cancer cells. Cancer-associated fibroblasts (CAFs) become synthetic machines that produce many different tumour components. CAFs have a role in creating extracellular matrix (ECM) structure and metabolic and immune reprogramming of the tumour microenvironment with an impact on adaptive resistance to chemotherapy. The pleiotropic actions of CAFs on tumour cells are probably reflective of them being a heterogeneous and plastic population with context-dependent influence on cancer.

The biology and function of fibroblasts in cancer

https://dash.harvard.edu/bitstream/handle/1/29293165/Cancer%20Nanotechnology.pdf?sequence=1

Cancer Nanotechnology: The impact of passive and active targeting in the era of modern cancer biology

Metastasis, the dissemination and growth of neoplastic cells in an organ distinct from that in which they originated, is the most common cause of death in cancer patients. This is particularly true for pancreatic cancers, where most patients are diagnosed with metastatic disease and few show a sustained response to chemotherapy or radiation therapy. Whether the dismal prognosis of patients with pancreatic cancer compared to patients with other types of cancer is a result of late diagnosis or early dissemination of disease to distant organs is not known. Here we rely on data generated by sequencing the genomes of seven pancreatic cancer metastases to evaluate the clonal relationships among primary and metastatic cancers. We find that clonal populations that give rise to distant metastases are represented within the primary carcinoma, but these clones are genetically evolved from the original parental, non-metastatic clone. Thus, genetic heterogeneity of metastases reflects that within the primary carcinoma. A quantitative analysis of the timing of the genetic evolution of pancreatic cancer was performed, indicating at least a decade between the occurrence of the initiating mutation and the birth of the parental, non-metastatic founder cell. At least five more years are required for the acquisition of metastatic ability and patients die an average of two years thereafter. These data provide novel insights into the genetic features underlying pancreatic cancer progression and define a broad time window of opportunity for early detection to prevent deaths from metastatic disease.

SF-010-4 Distant metastasis occurs late during the genetic evolution of pancreatic cancer

Depletion of Carcinoma-Associated Fibroblasts and Fibrosis Induces Immunosuppression and Accelerates Pancreas Cancer with Reduced Survival.

In recent years, cancer immunotherapy based on immune checkpoint inhibitors (ICIs) has achieved considerable success in the clinic. However, ICIs are significantly limited by the fact that only one third of patients with most types of cancer respond to these agents. The induction of cell death mechanisms other than apoptosis has gradually emerged as a new cancer treatment strategy because most tumors harbor innate resistance to apoptosis. However, to date, the possibility of combining these two modalities has not been discussed systematically. Recently, a few studies revealed crosstalk between distinct cell death mechanisms and antitumor immunity. The induction of pyroptosis, ferroptosis, and necroptosis combined with ICIs showed synergistically enhanced antitumor activity, even in ICI-resistant tumors. Immunotherapy-activated CD8+ T cells are traditionally believed to induce tumor cell death via the following two main pathways: (i) perforin-granzyme and (ii) Fas-FasL. However, recent studies identified a new mechanism by which CD8+ T cells suppress tumor growth by inducing ferroptosis and pyroptosis, which provoked a review of the relationship between tumor cell death mechanisms and immune system activation. Hence, in this review, we summarize knowledge of the reciprocal interaction between antitumor immunity and distinct cell death mechanisms, particularly necroptosis, ferroptosis, and pyroptosis, which are the three potentially novel mechanisms of immunogenic cell death. Because most evidence is derived from studies using animal and cell models, we also reviewed related bioinformatics data available for human tissues in public databases, which partially confirmed the presence of interactions between tumor cell death and the activation of antitumor immunity.

/pdf/ferroptosis-necroptosis-and-pyroptosis-in-anticancer-2p4imy222o.pdf

Ferroptosis, necroptosis, and pyroptosis in anticancer immunity

Cancer-associated fibroblasts (CAFs), a stromal cell population with cell-of-origin, phenotypic and functional heterogeneity, are the most essential components of the tumor microenvironment (TME). Through multiple pathways, activated CAFs can promote tumor growth, angiogenesis, invasion and metastasis, along with extracellular matrix (ECM) remodeling and even chemoresistance. Numerous previous studies have confirmed the critical role of the interaction between CAFs and tumor cells in tumorigenesis and development. However, recently, the mutual effects of CAFs and the tumor immune microenvironment (TIME) have been identified as another key factor in promoting tumor progression. The TIME mainly consists of distinct immune cell populations in tumor islets and is highly associated with the antitumor immunological state in the TME. CAFs interact with tumor-infiltrating immune cells as well as other immune components within the TIME via the secretion of various cytokines, growth factors, chemokines, exosomes and other effector molecules, consequently shaping an immunosuppressive TME that enables cancer cells to evade surveillance of the immune system. In-depth studies of CAFs and immune microenvironment interactions, particularly the complicated mechanisms connecting CAFs with immune cells, might provide novel strategies for subsequent targeted immunotherapies. Herein, we shed light on recent advances regarding the direct and indirect crosstalk between CAFs and infiltrating immune cells and further summarize the possible immunoinhibitory mechanisms induced by CAFs in the TME. In addition, we present current related CAF-targeting immunotherapies and briefly describe some future perspectives on CAF research in the end.

/pdf/crosstalk-between-cancer-associated-fibroblasts-and-immune-1htbn130xw.pdf

Crosstalk between cancer-associated fibroblasts and immune cells in the tumor microenvironment: new findings and future perspectives.

Carbon nanotubes in cancer diagnosis and therapy

LyP-1-conjugated nanoparticles for targeting drug delivery to lymphatic metastatic tumors.

Microbiota is just beginning to be recognized as an important player in carcinogenesis and the interplay among microbes is greater than expected. Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease for which mortality closely parallels incidence. Early detection would provide the best opportunity to increase survival rates. Specific well-studied oral, gastrointestinal, and intrapancreatic microbes and some kinds of hepatotropic viruses and bactibilia may have potential etiological roles in pancreatic carcinogenesis, or modulating individual responses to oncotherapy. Concrete mechanisms mainly involve perpetuating inflammation, regulating the immune system-microbe-tumor axis, affecting metabolism, and altering the tumor microenvironment. The revolutionary technology of omics has generated insight into cancer microbiomes. A better understanding of the microbiota in PDAC might lead to the establishment of screening or early-stage diagnosis methods, implementation of cancer bacteriotherapy, adjustment of therapeutic efficacy even alleviating the adverse effects, creating new opportunities and fostering hope for desperate PDAC patients.

/pdf/the-microbiota-and-microbiome-in-pancreatic-cancer-more-4i3sjup2ii.pdf

Jin Xu

Papers

Ferroptosis, necroptosis, and pyroptosis in anticancer immunity

Crosstalk between cancer-associated fibroblasts and immune cells in the tumor microenvironment: new findings and future perspectives.

Carbon nanotubes in cancer diagnosis and therapy

LyP-1-conjugated nanoparticles for targeting drug delivery to lymphatic metastatic tumors.

The microbiota and microbiome in pancreatic cancer: more influential than expected.