Resistance of human tumors to cancer chemotherapeutic agents: An important research problem

Bertino, Joseph R.

doi:10.1002/mpo.2950050117

Cited by 12 publications

(1 citation statement)

References 31 publications

(7 reference statements)

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“…One reason for this conundrum is that cancer biology remains incompletely understood. We have only a limited appreciation of important issues related to cancer diversity [1,2], heterogeneity [3][4][5][6][7][8][9][10][11][12], and resistance to therapy [13][14][15][16], as well as those leading to failed pretreatment strategies [17], and sensitivity testing [18]. Thus far, only a small proportion of cancer patients have truly benefitted from existing therapies [19].…”

Section: Introductionmentioning

confidence: 99%

Epistemology of the Origin of Cancer II: Fibroblasts Are the First Cells to Undergo Neoplastic Transformation

2023

Cell Physiol Biochem

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Background/Aims: Many questions in cancer biology remain unanswered. Perhaps the most important issues remaining to be addressed focus on the molecular basis of carcinogenesis. Today’s cancer focus lies on genetics and gene expression, which is unlikely to explain the true cause of most cancers or lead to a cure. Methods: Earlier, we provided a plausible mechanism for this process, specifically, that most cancers develop in response to pathogenic stimuli that induce chronic inflammation, fibrosis, and remodeling of the cellular microenvironment. Collectively, these changes generate a precancerous niche (PCN) in which fibrosis and remodeling are ongoing secondary to persistent inflammation, followed by the deployment of a chronic stress escape strategy (CSES). If the CSES is unsuccessful, the cell undergoes a normal cell to cancer cell transformation (NCCT). Results: Here, we highlight the critical role of fibroblasts as the first cells to undergo neoplastic transformation to a cancerous phenotype which is based on several critical findings. First, persistent disruption of homeostatic crosstalk increases lysyl oxidase activity and lysine oxidation which leads to increased collagen stiffness and decreased elasticity. If unresolved, chronic tissue stress will lead to an escape strategy that involves the recruitment of fibroblasts and fibrocytes from the bone marrow as well as cells undergoing an epithelial-mesenchymal transition (EMT). This yields a heterogeneous pool of cells that express both epithelial and mesenchymal markers and that will ultimately differentiate into cancer-associated fibroblasts (CAFs). Finally, CAFs undergo a mesenchymal-epithelial transition (MET) and express epithelial markers that facilitate their integration into the target tissue. Conclusion: Here, we review the published findings that led us to this conclusion which is the most plausible answer to this critical question.

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Section: Introductionmentioning

confidence: 99%

Epistemology of the Origin of Cancer II: Fibroblasts Are the First Cells to Undergo Neoplastic Transformation

2023

Cell Physiol Biochem

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Establishment of three bleomycin-resistant human carcinoma cell lines and their cross-resistance to other antitumor agents

Urade

Sugi

Miyazaki

1988

Cancer

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Three bleomycin-resistant (BLMr) human carcinoma cell lines (HeLa-BLMr, KB-BLMr, and Hepd-uvBLMr) were established in culture by progressively increasing the concentration of bleomycin (BLM). HeLa-BLMr and KB-BLMr were obtained after 5 and 2 months of incubation with BLM, whereas the establishment of Hepd-uvBLMr required 3 months of incubation with BLM after ultraviolet treatment. These cells have been successfully subcultured for more than 150 passages during more than 2 years in the presence of 1 microgram/ml of BLM. The degrees of BLM resistance were 20-fold, 11.6-fold, and 186-fold for HeLa-BLMr, KB-BLMr, and Hepd-uvBLMr, respectively, and the resistant phenotype of both HeLa-BLMr and Hepd-uvBLMr was stable when they were cultured for 30 passages in BLM-free medium, but unstable in KB-BLMr. Although each cell line exhibited cross-resistance to 3 to 5 other antitumor agents including peplomycin, combined use of BLM with a polyene antibiotic, a calcium channel blocker, or a poly(ADP-ribose) polymerase inhibitor overcame the BLM resistance in vitro to various degrees.

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Das Bronchuskarzinom

Wilde¹,

Gabler²,

Dürschmied³

et al. 1985

Tumoren Der Atmungsorgane Und Des Mediastinums B

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Resistance of human tumors to cancer chemotherapeutic agents: An important research problem

Cited by 12 publications

References 31 publications

Epistemology of the Origin of Cancer II: Fibroblasts Are the First Cells to Undergo Neoplastic Transformation

Epistemology of the Origin of Cancer II: Fibroblasts Are the First Cells to Undergo Neoplastic Transformation

Establishment of three bleomycin-resistant human carcinoma cell lines and their cross-resistance to other antitumor agents

Das Bronchuskarzinom

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