The Colorectal Cancer Tumor Microenvironment and Its Impact on Liver and Lung Metastasis

Chandra, Ramesh; Karalis, John D.; Liu, C.; Murimwa, Gilbert Z.; Park, Josiah Voth; Heid, Christopher A.; Reznik, Scott I.; Huang, Emina H.; Minna, John D.; Brekken, Rolf A.

doi:10.3390/cancers13246206

Cited by 87 publications

(63 citation statements)

References 224 publications

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“…Pericytes, residing at the interface between the endothelium and interstitium, mostly contribute to inflammation-associated fibrosis, whereas their role in IBD [ 43 ], as well as CRC, is not fully understood. Interestingly, earlier studies suggest a functional relevance in the tumor microenvironment and a potential involvement in antiangiogenic therapies [ 44 ].…”

Section: Discussionmentioning

confidence: 99%

Cell Type-Specific Induction of Inflammation-Associated Genes in Crohn’s Disease and Colorectal Cancer

Saul

Barros

Wixom

et al. 2022

IJMS

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Based on the rapid increase in incidence of inflammatory bowel disease (IBD), the identification of susceptibility genes and cell populations contributing to this condition is essential. Previous studies suggested multiple genes associated with the susceptibility of IBD; however, due to the analysis of whole-tissue samples, the contribution of individual cell populations remains widely unresolved. Single-cell RNA sequencing (scRNA-seq) provides the opportunity to identify underlying cellular populations. We determined the enrichment of Crohn’s disease (CD)-induced genes in a publicly available Crohn’s disease scRNA-seq dataset and detected the strongest induction of these genes in innate lymphoid cells (ILC1), highly activated T cells and dendritic cells, pericytes and activated fibroblasts, as well as epithelial cells. Notably, these genes were highly enriched in IBD-associated neoplasia, as well as sporadic colorectal cancer (CRC). Indeed, the same six cell populations displayed an upregulation of CD-induced genes in a CRC scRNA-seq dataset. Finally, after integrating and harmonizing the CD and CRC scRNA-seq data, we demonstrated that these six cell types display a gradual increase in gene expression levels from a healthy state to an inflammatory and tumorous state. Together, we identified cell populations that specifically upregulate CD-induced genes in CD and CRC patients and could, therefore, contribute to inflammation-associated tumor development.

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Section: Discussionmentioning

confidence: 99%

Cell Type-Specific Induction of Inflammation-Associated Genes in Crohn’s Disease and Colorectal Cancer

Saul

Barros

Wixom

et al. 2022

IJMS

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“…Metastasis is a multistep process of intravasation, survival in blood, extravasation and colonization of cancer cells ( Sahai, 2007 ). The interaction be-tween the tumor and the TME is known to play a key role in the success or failure of those metastatic processes ( Fontebasso and Dubinett, 2015 ; Chandra et al, 2021 ). Accordingly, many recent studies emphasize the importance of the TME as a therapeutic target ( Steeg, 2016 ; Fares et al, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

CGX, a standardized herbal syrup, inhibits colon-liver metastasis by regulating the hepatic microenvironments in a splenic injection mouse model

2022

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Background: Colon-liver metastasis is observed in approximately 50% of patients with colorectal cancer and is a critical risk factor for a low survival rate. Several clinical studies have reported that colon-liver metastasis is accelerated by pathological hepatic microenvironments such as hepatic steatosis or fibrosis. Chunggan syrup (CGX), a standardized 13-herbal mixture, has been prescribed to patients with chronic liver diseases, including fatty liver, inflammation and fibrotic change, based on preclinical and clinical evidence.Aim of the study: In the present study, we investigated anti-liver metastatic the effects of CGX in a murine colon carcinoma (MC38)-splenic injection mouse model.Materials and methods: C57BL/6N mice were administered with CGX (100, 200 or 400 mg/kg) for 14 days before or after MC38-splenic injection under normal and high-fat diet (HFD) fed conditions. Also, above experiment was repeated without MC38-splenic injection to explore underlying mechanism.Results: The number of tumor nodules and liver weight with tumors were sup-pressed by preadministration of CGX in both normal and HFD fed mice. Regarding its mechanisms, we found that CGX administration significantly activated epithelial-cadherin (E-cadherin), but decreased vascular endothelial-cadherin (VE-cadherin) in hepatic tissues under MC38-free conditions. In addition, CGX administration significantly reduced hepatic steatosis, via modulation of lipolytic and lipogenic molecules, including activated adenosine monophosphate activated protein kinase (AMPK) and peroxisome proliferator activated receptor-alpha (PPARα).Conclusion: The present data indicate that CGX exerts an anti-colon-liver metastatic property via modulation of hepatic lipid related microenvironments.

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“…Neutrophils' tumor trophic function is seen across the common cancers [67][68][69][70][71][72][73][74]. Dapsone is an old sulfone antibiotic that has seen a recent revival of use in treating cancer and nonmalignant neutrophilic dermatoses [75][76][77][78][79].…”

Section: Dapsonementioning

confidence: 99%

MDACT: A New Principle of Adjunctive Cancer Treatment Using Combinations of Multiple Repurposed Drugs, with an Example Regimen

Kast¹,

Alfieri

Assi

et al. 2022

Cancers

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In part one of this two-part paper, we present eight principles that we believe must be considered for more effective treatment of the currently incurable cancers. These are addressed by multidrug adjunctive cancer treatment (MDACT), which uses multiple repurposed non-oncology drugs, not primarily to kill malignant cells, but rather to reduce the malignant cells’ growth drives. Previous multidrug regimens have used MDACT principles, e.g., the CUSP9v3 glioblastoma treatment. MDACT is an amalgam of (1) the principle that to be effective in stopping a chain of events leading to an undesired outcome, one must break more than one link; (2) the principle of Palmer et al. of achieving fractional cancer cell killing via multiple drugs with independent mechanisms of action; (3) the principle of shaping versus decisive operations, both being required for successful cancer treatment; (4) an idea adapted from Chow et al., of using multiple cytotoxic medicines at low doses; (5) the idea behind CUSP9v3, using many non-oncology CNS-penetrant drugs from general medical practice, repurposed to block tumor survival paths; (6) the concept from chess that every move creates weaknesses and strengths; (7) the principle of mass—by adding force to a given effort, the chances of achieving the goal increase; and (8) the principle of blocking parallel signaling pathways. Part two gives an example MDACT regimen, gMDACT, which uses six repurposed drugs—celecoxib, dapsone, disulfiram, itraconazole, pyrimethamine, and telmisartan—to interfere with growth-driving elements common to cholangiocarcinoma, colon adenocarcinoma, glioblastoma, and non-small-cell lung cancer. gMDACT is another example of—not a replacement for—previous multidrug regimens already in clinical use, such as CUSP9v3. MDACT regimens are designed as adjuvants to be used with cytotoxic drugs.

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The Colorectal Cancer Tumor Microenvironment and Its Impact on Liver and Lung Metastasis

Cited by 87 publications

References 224 publications

Cell Type-Specific Induction of Inflammation-Associated Genes in Crohn’s Disease and Colorectal Cancer

Cell Type-Specific Induction of Inflammation-Associated Genes in Crohn’s Disease and Colorectal Cancer

CGX, a standardized herbal syrup, inhibits colon-liver metastasis by regulating the hepatic microenvironments in a splenic injection mouse model

MDACT: A New Principle of Adjunctive Cancer Treatment Using Combinations of Multiple Repurposed Drugs, with an Example Regimen

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