Enhancing an Oxidative “Trojan Horse” Action of Vitamin C with Arsenic Trioxide for Effective Suppression of KRAS-Mutant Cancers: A Promising Path at the Bedside
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Stage 4 Pancreatic Cancer
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Cancer Early Detection Advanced Research Center, Knight Cancer Institute, Oregon Health & Science University, 2720 SW Moody Ave., Portland, OR 97201, USA
Department of Molecular and Medical Genetics, Oregon Health & Science University School of Medicine, 3222 SW Research Drive, Portland, OR 97239, USA
Pancreatic Cancer: The Main Points To Know About This Uncommon Disease
Pancreatic cancer is a disease notorious for its high frequency of recurrence and low survival rate. Surgery is the most effective treatment for localized pancreatic cancer, but most cancer recurs after surgery, and patients die within ten years of diagnosis. The question persists: what makes pancreatic cancer recur and metastasize with such a high frequency? Herein, we review evidence that subclinical dormant pancreatic cancer cells disseminate before developing metastatic or recurring cancer. We then discuss several routes by which pancreatic cancer migrates and the mechanisms by which pancreatic cancer cells adapt. Lastly, we discuss unanswered questions in pancreatic cancer cell migration and our perspectives.
Despite extensive efforts toward developing treatments, the outcome for patients with pancreatic ductal adenocarcinoma (PDAC) remains poor [1]. A leading cause of poor prognosis is frequent recurrence [2, 3, 4, 5]. Surgery is currently the most effective treatment for localized PDAC. However, most patients experience local or distant recurrence after undergoing potentially “curative” surgery, and 95% of these patients die within ten years of diagnosis [2, 3, 4, 5]. The early resectable small T1 stage of PDAC is inferred to progress to the T4 stage in just over one year [6]. Systemic dissemination of dormant PDAC cells occurs before developing into local recurrence or metastases [7, 8, 9, 10]. The dissemination of radiographically undetectable cancer cells currently limits the ability to cure PDAC patients. Why does PDAC have such high cell dissemination, and what types of cell migration exist?
Cell movement (or migration) is essential in embryogenesis, wound healing, host infection, angiogenesis, and carcinogenesis. For example, immune cells migrate through chemotaxis [11, 12], neural cells through axon guidance signals and neurotrophins [13, 14], and fibroblast cells through the actin-based cytoskeleton [15, 16, 17, 18]. Epithelial cells are not mobile in general. However, several exceptions are observed where stationary epithelial cells can migrate. The first exception is observed during embryogenesis, such as when a primitive streak is formed to initiate the formation of three germ layers (gastrulation) [19]. The second exception is observed during wound healing after tissue injury [20]. Lastly, it is observed in carcinogenesis [21, 22]. This review will highlight the epithelial cell movement in pancreatic cancer, which can be a basis for understanding highly recurrent diseases. First, we introduce the evidence for subclinical pancreatic cancer cell dissemination and the organs to which pancreatic cancers metastasize. Next, we discuss the type of cell migrations frequently observed in pancreatic cancer, followed by molecular mechanisms and mediators that lead to such cell dissemination. Lastly, we discuss unanswered questions and potential therapeutic targets.
Types Of Pancreatic Cancer
PDAC is a disease notorious for its high frequency of local and distal metastases. When then, do such metastases occur during disease progression? PDAC is believed to initiate from several preneoplastic lesions with ductal morphology such as pancreatic intraepithelial neoplasia (PanINs), intraductal papillary mucinous neoplasias (IPMNs), and mucinous cystic neoplasias (MCNs) [23]. PanINs are the most common precursor lesion in human and are classified as low grade (PanIN1 and 2) and high grade (PanIN3) based on cytologic atypia severity [23]. Low-grade PanINs are clinically benign, whereas high-grade PanIN3, usually found in pancreata with PDAC, is considered carcinoma in situ [23]. Most PanIN1 lesions (>90%) have activating mutations in the KRAS gene [24], and PanIN2 lesions already have genetic alterations in KRAS, CDKN2A, and TP53, which are typically seen in PDAC [24, 25].
Murine PDAC models [26, 27, 28], in which pancreata carry the Kras mutant alleles (KrasG12D) and/or inactivation of tumor suppressors such as p53 and Cdkn2a, recapitulated disease progression and significantly improved our understanding of PDAC cell migration. In a landmark paper, Rhim et al. showed that pancreatic cancer could be disseminated early in KPCY mice (Pdx1-Cre; Kras
; Rosa-YFP) [10]. They showed a subset of YFP-labeled cells to intermingle with stroma cells, even in the PanINs stages. Further, YFP cell populations were observed in distal organs, such as the liver [10], suggesting that the early disseminating pancreatic cancer cells can be spread out to distal organs without clinical symptoms or forming cancers.
Pdf) Cancer Registry Report In Mansoura University Hospital, Egypt In 2015
Another murine PDAC study by Pommier et al., also showed that the liver contained dormant, single disseminated cancer cells that had unusual phenotypes with cytokeratin 19 (CK19)-negative and major histocompatibility complex class I (MHC1) [9]. In that paper, to further identify the cell-autonomous “switch” regulating the development of metastatic states in primary tumors, they performed single cell RNAseq on in vitro-sorted E-Cadherin- and E-Cadherin+ cells. They found that unresolved endoplasmic reticulum (ER) stress reduced E-cad and MHC1 expression post-transcriptionally in a subset of primary PDAC. As a result, T cells ended up selecting dormant single disseminated cancer cells by eliminating MHC1+ proliferating cells in the livers of naïve and pre-immunized mice, intrasplenically injected with murine metastatic PDAC [9].
In humans, several studies also indicated the presence of systemic dissemination of pancreatic cancer before clinical diagnosis of metastasis, through computational modeling, exome sequencing, and clinicopathological analysis [7, 8, 9, 29]. Pommier et al. also confirmed the presence of single dormant cancer cells through clinicopathological analysis. They showed that these cells lack expression of CK19 and MHC1 in the livers of patients with PDAC who had no clinically detectable hepatic metastases [9].
Haeno et al. investigated the growth of each cancer and its metastatic probability using two independent databases for a total of 228 PDAC patients: (i) autopsy cohort (n = 101) and (ii) adjuvant cohort (n = 127) [7]. In the autopsy cohort, data on primary tumor size and metastatic burden were recorded for each patient at diagnosis and autopsy. In addition, approximately half of the patients (n = 47) had at least one intermediate time point between diagnosis and autopsy to investigate primary tumor size, local and distant recurrence, and metastases. In the adjuvant cohort, data were recorded for patients who received curative surgeries and adjuvant chemotherapy and radiation therapy. To investigate the growth of each cancer and its metastatic probability, they developed a stochastic exponential mathematical model of PDAC progression and dissemination, with the assumption that metastatic ability is a consequence of a single genetic or epigenetic change and that mutation and dissemination are likely separated in time. Using this stochastic exponential model, they investigated the probability that metastatic cells, as well as cells with the potential to metastasize, are present at the time of diagnosis. They found that not all patients are expected to present with metastatic disease at diagnosis. However, intriguingly, their analysis indicates that all patients can harbor “metastasis-enabled cells” in the primary tumor at the time of diagnosis, even when the primary tumor size is small [7].
Intravital Imaging Technology Guides Fak Mediated Priming In Pancreatic Cancer Precision Medicine According To Merlin Status
Sakamoto et al. performed whole-exome and targeted sequencing of resected primary tumors and matched intrapancreatic recurrences or distant metastases from autopsied tumors from 10 patients with PDAC [8]. Phylogenic studies inferred two distinct evolutionary trajectories by which recurrent disease arose. One group represented the recurrent disease developed from a single residual clonal population (“monophyletic origin”). The other group represented the recurrent diseases seeded by multiple ancestral clones (“polyphyletic origin”). Pairwise Jaccard similarity coefficients for all samples in each patient indicated that monophyletic recurrences were significantly more distant from the primary tumor. In contrast, polyphyletic recurrences were highly related to the primary tumors.
Utilizing mathematical modeling and previously measured metastatic doubling times, they found that the minimum time required to grow from one to a billion cells is 1.82 years. Because clinical metastases occurred much earlier than the required 1.82 years after surgery in patients with the distant disease (6–18 months), at least one of the metastases must have been microscopically seeded before surgery. Their analysis further indicated that recurrent tumors were diverse depending
PDAC is a disease notorious for its high frequency of local and distal metastases. When then, do such metastases occur during disease progression? PDAC is believed to initiate from several preneoplastic lesions with ductal morphology such as pancreatic intraepithelial neoplasia (PanINs), intraductal papillary mucinous neoplasias (IPMNs), and mucinous cystic neoplasias (MCNs) [23]. PanINs are the most common precursor lesion in human and are classified as low grade (PanIN1 and 2) and high grade (PanIN3) based on cytologic atypia severity [23]. Low-grade PanINs are clinically benign, whereas high-grade PanIN3, usually found in pancreata with PDAC, is considered carcinoma in situ [23]. Most PanIN1 lesions (>90%) have activating mutations in the KRAS gene [24], and PanIN2 lesions already have genetic alterations in KRAS, CDKN2A, and TP53, which are typically seen in PDAC [24, 25].
Murine PDAC models [26, 27, 28], in which pancreata carry the Kras mutant alleles (KrasG12D) and/or inactivation of tumor suppressors such as p53 and Cdkn2a, recapitulated disease progression and significantly improved our understanding of PDAC cell migration. In a landmark paper, Rhim et al. showed that pancreatic cancer could be disseminated early in KPCY mice (Pdx1-Cre; Kras
; Rosa-YFP) [10]. They showed a subset of YFP-labeled cells to intermingle with stroma cells, even in the PanINs stages. Further, YFP cell populations were observed in distal organs, such as the liver [10], suggesting that the early disseminating pancreatic cancer cells can be spread out to distal organs without clinical symptoms or forming cancers.
Pdf) Cancer Registry Report In Mansoura University Hospital, Egypt In 2015
Another murine PDAC study by Pommier et al., also showed that the liver contained dormant, single disseminated cancer cells that had unusual phenotypes with cytokeratin 19 (CK19)-negative and major histocompatibility complex class I (MHC1) [9]. In that paper, to further identify the cell-autonomous “switch” regulating the development of metastatic states in primary tumors, they performed single cell RNAseq on in vitro-sorted E-Cadherin- and E-Cadherin+ cells. They found that unresolved endoplasmic reticulum (ER) stress reduced E-cad and MHC1 expression post-transcriptionally in a subset of primary PDAC. As a result, T cells ended up selecting dormant single disseminated cancer cells by eliminating MHC1+ proliferating cells in the livers of naïve and pre-immunized mice, intrasplenically injected with murine metastatic PDAC [9].
In humans, several studies also indicated the presence of systemic dissemination of pancreatic cancer before clinical diagnosis of metastasis, through computational modeling, exome sequencing, and clinicopathological analysis [7, 8, 9, 29]. Pommier et al. also confirmed the presence of single dormant cancer cells through clinicopathological analysis. They showed that these cells lack expression of CK19 and MHC1 in the livers of patients with PDAC who had no clinically detectable hepatic metastases [9].
Haeno et al. investigated the growth of each cancer and its metastatic probability using two independent databases for a total of 228 PDAC patients: (i) autopsy cohort (n = 101) and (ii) adjuvant cohort (n = 127) [7]. In the autopsy cohort, data on primary tumor size and metastatic burden were recorded for each patient at diagnosis and autopsy. In addition, approximately half of the patients (n = 47) had at least one intermediate time point between diagnosis and autopsy to investigate primary tumor size, local and distant recurrence, and metastases. In the adjuvant cohort, data were recorded for patients who received curative surgeries and adjuvant chemotherapy and radiation therapy. To investigate the growth of each cancer and its metastatic probability, they developed a stochastic exponential mathematical model of PDAC progression and dissemination, with the assumption that metastatic ability is a consequence of a single genetic or epigenetic change and that mutation and dissemination are likely separated in time. Using this stochastic exponential model, they investigated the probability that metastatic cells, as well as cells with the potential to metastasize, are present at the time of diagnosis. They found that not all patients are expected to present with metastatic disease at diagnosis. However, intriguingly, their analysis indicates that all patients can harbor “metastasis-enabled cells” in the primary tumor at the time of diagnosis, even when the primary tumor size is small [7].
Intravital Imaging Technology Guides Fak Mediated Priming In Pancreatic Cancer Precision Medicine According To Merlin Status
Sakamoto et al. performed whole-exome and targeted sequencing of resected primary tumors and matched intrapancreatic recurrences or distant metastases from autopsied tumors from 10 patients with PDAC [8]. Phylogenic studies inferred two distinct evolutionary trajectories by which recurrent disease arose. One group represented the recurrent disease developed from a single residual clonal population (“monophyletic origin”). The other group represented the recurrent diseases seeded by multiple ancestral clones (“polyphyletic origin”). Pairwise Jaccard similarity coefficients for all samples in each patient indicated that monophyletic recurrences were significantly more distant from the primary tumor. In contrast, polyphyletic recurrences were highly related to the primary tumors.
Utilizing mathematical modeling and previously measured metastatic doubling times, they found that the minimum time required to grow from one to a billion cells is 1.82 years. Because clinical metastases occurred much earlier than the required 1.82 years after surgery in patients with the distant disease (6–18 months), at least one of the metastases must have been microscopically seeded before surgery. Their analysis further indicated that recurrent tumors were diverse depending
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