Cancer Research and Molecular Mechanisms-Sci Forschen

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The Initial Emergence Phenomenon in Patterned Carcinogenesis in Lung Neoplasia

  Lawrence M Agius*   

Department of Pathology, Mater Dei Hospital, Tal-Qroqq, University of Malta Medical School, Msida, Malta

*Corresponding author: Lawrence M Agius, Department of Pathology, Mater Dei Hospital, Tal-Qroqq, University of Malta Medical School, Msida, Malta, Tel: 356-21451752; E-mail:


Personalized attributes of a given neoplasm within a given individual patient attest to the highly specific emergence stage as reflected and further evidenced by patterns of evolution and de-evolution of stem cells and of their immediate progenitor cells. Constitutional determination is an incremental degree of sensitivity as borne out by given variants of histologically evolving carcinomatous types and as further involved by metastatic spread within the body. Determined patterns of constitution are induction phenomena in their own right and further conform to the emergence phase as central to any further instituted dimensions of cell multiplication, growth and spread of the malignant cells. It is in terms of such emerging patterns that constitutional parameters of progression are inherently linked to hierarchically determined systems for further patterned progression and spread of the malignant cells.


Lung cancer is a highly heterogenous group of diseases that at multiple levels of diagnosis, prevention and attempted therapeutics constitutes a semblance modality for the elimination of sundry entities related to either smoking or non-smoking. The proportion of female patients with lung cancer who can undergo surgery has increased significantly [1]. In such scenario, the distributional frequency is high and constitutes in many Western countries the most frequently encountered form of neoplasia. It is further to such assessment that multiple hereditary and acquired forms of tumorigenesis constitute the emergence of lung epithelial damage as seen most often in smokers towards the progression of invasive non-small-cell and small-cell carcinomas with significantly personalized signature markers in the individual patient. Inflammation is associated with lung cancer [2]. Cyclooxygenase-2 is over expressed in lung cancer and mediates prostaglandin synthesis that plays a central role in the inflammatory response [3]. Intra-tumoral heterogeneity of CD4+ and CD8+ tumor infiltrating lymphocytes has been observed in tumor centres versus margins and also corresponding association with prognosis in lung adenocarcinoma patients [4].


The emergence of a highly frequent form of neoplasia is indicative of the interplay of suppressor and oncogene sets of genes in a manner that further validates increments of incidence as a direct result of the establishment of hallmarks of neoplasia such as growth-factor independence, growth-factor-inhibitor insensitivity, and evasion of apoptosis, angiogenesis, invasion and metastatic spread. There are both microbiome-gene and microbiome-exposure interactions in squamous cell carcinoma lung cancer tissue. Specifically, tumors harbouring TP53 mutations show a unique bacterial consortium that is higher in relative abundance in smoking-associated tumors [5]. It is further to such contractual setting parameters that the inclusive dimensions for neoplasia can potentially constitute model systems of malignant change as projected in general terms. Live cell Raman micro-spectroscopy is an important bioanalytical technique for labelfree discrimination of a range of different cells types (as in cancer cells and fibroblasts) and behaviors (e.g apoptosis) [6]. The recognition, for example, of adenocarcinoma, often not associated with smoking, is further dimensional context for the evidential reconstitution of multiple molecular pathways. STAT3 shows context-dependency and is a master regulator of epithelial identity and KRAS-driven tumorigenesis [7].

The incremental index frequency of NSCLC and of other forms of lung neoplasia is also exemplified by neuro endocrine tumors and broncho-alveolar tumors that constitute the persistent operability of active molecular pathways closely allied to substantial epithelial cell damage in various component anatomic regions of the lung. Tumor viruses may potentially play a role in non-small-cell lung cancer by regulating host genes in tumor cells during neoplastic differentiation and progression [8]. The development re-appraisal dimensions of NOTCH, HEDGEHOG are incremental in terms of a stem cell response of aberrant proportions in the acquisition of further injury to lung epithelial cells. Indeed, persistence of cell injury constitutes a selfrealization of such injury as originator of aberrant molecular pathways involving diverse ligand-receptor stimulation. Isocitrate dehydrogenase 2 promotes the Warburg effect and lung cancer cell growth, which is mediated through HIF1alpha activation followed by decreased alphaketoglutamate [9]. It is within such context that the full significance of carcinogenesis attests to a global transformation of the epithelial cell within systems of progression and further transformation. Smoking alone cannot completely explain the lung cancer etiology; altered lung microbiome and chronic inflammatory insult in lung tissues contribute to carcinogenesis with PARP1 being unregulated in nonsmall cell lung cancer through the action of the cyanobacterial toxin microcystin [10].


Transforming growth factor-beta is the most potent inducer of epithelial-mesenchymal transition in non-small cell lung cancer cells and is pivotal to the development of tumor-promoting microenvironment in lung cancer tissue [11]. The complex interplay of such indices indicates the realization of sub-fractional cooperative pathways that specifically target intermediary molecular substrates as attested especially by ligand-receptor binding. Constitutive dimensions are context defining in terms that further collaborate in terms that augment realization of parametric indices, as wellexemplified by the incremental aggressiveness of multiple forms of lung neoplasia that account for dimensional spread to various body organs. Down-regulated Gasdermin D attenuates tumor proliferation via the intrinsic mitochondrial apoptotic pathway and inhibition of EGFR/Akt signaling and predicts a good prognosis in non-small cell lung cancer [12]. It is further to such considerations that lung tumorigenesis constitutes a highly characterized series of dimensional modeling that is wholly organ-centered in targeting other organs in metastatic spread..

Exquisite origin from damaged lung epithelial cells is hence a central cooperative emergence of multiple types of potential tumorigenesis that incrementally constitutes the delivery of novel operative pathways that target the stem cell and its immediate progenitor cells.

Gamma-secretase inhibitors target the Notch pathway and gamma secretase is a potential biomarker for sensitivity as single agents or as sensitisers of non small cell lung cancer to cytotoxic and targeted therapies [13]. In terms therefore of the constitutive susceptibilities for malignant cells, the resultant re-appraisal of dimensions for further transformation is reflected in the substantial progressive transformation as malignantly spreading neoplasms. Expression of phosphatase and tension homolog and programmed cell death ligand 1 has been observed in adenosquamous carcinoma of the lung [14].

Potential Carcinogenesis

The emergence of potential carcinogenesis in patients who have ceased smoking over 5 years previously allows for the further cooperative re-distribution of carcinogenetic influence in terms of agent-directed targeting of specific subsets of epithelial cell cohorts. Such distributional patterns are central to a concept that damage to lung epithelial cells is itself a specialized modality in its own right in terms ranging from intracellular milieu to extra-cellular tissue microenvironment. Inhibition of ataxia telangiectasia and Rad4- related kinase down regulates PD-L1 and sensitises tumor cells to T-cell-mediated killing [15]. It is also significant to consider unit and sub-unit dimensions in terms that further refine the targeting modalities of operability within systems of circulatory and biologic sustainability parametric control.

Component sub-units

Recent studies suggest that individual subunits of chromatinremoving complexes generate epigenetically specific signaling in tumorigenicity [16]. Component sub-units include the diversity of the malignant transformation process in terms that further augment the realization of an essential emergence step beyond the re-appraisal of systems of parametric control. In such manner, constitutive attributes denote the system emergence of a carcinogenetic event in terms that constitute imaged dimensions for progression of such carcinogenesis. It is within context-formulation patterns that an emergence step of the tumor both implicates and further confirms the realization of personalized signature pathways that are molecularly aberrant. MUC5AC, a gel forming mucin, is required in KRAS-dependent lung carcinogenesis [17]. Molecular pathways are hence novel and aberrant moieties that target the incremental formulation of injury to the original cell epithelium of the lung. Lower expression of Reticulon-4 (commonly known as a neurite outgrowth inhibitor, Nogo) is associated with significantly better survival in lung, breast, cervical and renal cancer patients by dysregulating the AKT pathway, destabilising the cytoskeleton, and enhancing paclitaxel-induced cytotoxicity [18].

Contextual origin

Contextual idealization of the cells of origin attains further significant import within systems of patterned distribution and re-distribution of potential carcinogenic agents in progressive transformation. Eukaryotic translation initiation factor 6 when depleted in adenocarcinoma and squamous cell carcinoma lung cancer cell lines inhibits cell proliferation and induces apoptosis [19]. The patterns of inclusive realization are based on tumor emergence dynamics and include the performance dynamics also of the stem cell biologic system. It is highly significant to conclude that the involvement of parameters specifically patterns modules of response to the injurious agent or agents in the performance of dynamics of institution. Micro-RNAs play an important role in lung carcinogenesis and progression; single-nucleotide polymorphisms in miRNA involved in miRNA biogenesis and structural alteration may impact miRNA expression [20].

Dynamics of constitutional operability are inherited predispositioned patterns as reflected in the concept of stem cell biology and as further confirmed by the cooperative index for operative emergence of a tumor that carries personalized signatures in molecular pathway institution and progression. The aberrant patterns of such emerging neoplasms is brought towards the dimensional reconstitution of cell identity in terms of specifically aberrant determination as indeed realized by stem cell constitution.

Concluding Remarks

Performance reconstitution is a specific induction response in patterned carcinogenesis as well exemplified by lung neoplasia and as further outlined by constitutional identity of specific cohorts of stem cells and their immediate progenitor cells. In the identification of injury to premalignant patterns of emergence, the neoplasm is further characterized by dimensions of progressive spread. Indices for the characterization of the malignant cells may be further categorized as a whole series of further re-characterizations as evidenced by a specific targeting in emergence phase dynamics. The inclusion of realized stereotype formulas would indeed include patterned reappraisal in further conformational identity in terms of personalized signature formulas of a given lung neoplasm.


  1. Ji X, Fang Y, Liu J (2018) Analysis of the clinicopathological characteristics and their trends among patients with lung cancer undergoing surgery in a tertiary cancer hospital of north China during 2000-2013. J Thorac Dis 10: 3973-3982. [Ref.]
  2. Erikson P, Gardner LD, Loffredo CA, St George DM, Bowman ED, et al. (2018) Racial and ethnic differences in the relationship between aspirin use and non-small cell lung cancer risk and survival. Cancer Epidemiol Biomarkers Prev. [Ref.]
  3. Li J, Lu X, Zou X, Jiang Y, Yao J, et al. (2018) COX-2 rs5275 and rs689466 polymorphism and risk of lung cancer: a PRISMA-compliant metaanalysis. Medicine (Baltimore) 97: e11859. [Ref.]
  4. Zhang C, Ding H, Huang H, Heyilimu P, Miao Y, et al. (2018) TCR repertoire intratumor heterogeneity of CDR+ and CD8+ in centres and margins of localised lung adenocarcinomas. Int J Cancer. [Ref.]
  5. Greenhouse KL, White JR, Vargas AJ, Bliskovsky VV, Beck JA, et al. (2018) Interaction between the micro biome and TP53 in human lung cancer. Genome Biol 19: 123. [Ref.]
  6. Surmacki JM, Woodhams BJ, Haslehurst A, Ponder BAJ, Bohndiek SE (2018) Raman micro-spectroscopy for accurate identification of primary human bronchial epithelial cells. Sci Rep 8: 12604. [Ref.]
  7. D’Amico S, Shi J, Martin BL, Crawford HC, Petrenko O, et al. (2018) STAT3 is a master regulator of epithelial identity and KRAS-driven tumorigenesis. Genes&Dev 32: 1175. [Ref.]
  8. Kim Y, Pierce CM, Robinson LA (2018) Impact of viral presence in tumor on gene expression in non-small cell lung cancer. BMC Cancer 18: 843. [Ref.]
  9. Li J, He Y, Tan Z, Lu J, Li L, et al. (2018) Wild-type IDH2 promotes the Warburg effect and tumor growth through HIF1alpha in lung cancer. Theranostics 8: 4050-4061. [Ref.]
  10. Apopa PL, Alley L, Penney RB, Arnaoutakis K, Stelige MA, et al. (2018) PARP1 is up-regulated in non-small cell lung cancer tissues in the presence of the cyanobacterias toxin microcystin. Front Microbial 9: 1757. [Ref.]
  11. Saito A, Horie M, Nagase T (2018) TGF-Beta signaling in lung health and disease. Int J Mol Sci 19: 2460. [Ref.]
  12. Gao J, Qiu X, Xi G, Liu H, Zhang F, et al. (2018) Downregulation of GSDMD attenuates tumor proliferation via the intrinsic mitochondrial apoptotic pathway and inhibition of EGFR/Akt singling and predicts a good prognosis in non-small cell lung cancer. Oncol Rep 40: 1971-1984. [Ref.]
  13. Pine SR (2018) Rethinking gamma-secretase inhibitors for treatment of non-small cell lung cancer: is Notch the target. Clin Cancer Res. [Ref.]
  14. Hlaing AM, Furusato B, Udo E, Kitamura Y, Souda M, et al. (2018) Expression of phosphatase and tennis homolog and programmed cell death ligand 1 in adenosquamous carcinoma of the lung. Biochem Biophys Res Commun 18: 2764-2769. [Ref.]
  15. Sun LL, Yang RY, Li CW, Chen MK, Shao B, et al. (2018) Inhibition of ATR down regulates PD-L1 and sensitises tumor cells to T-cellmediated killing. Am J Cancer Res 8: 1307-1316. [Ref.]
  16. Mao C, Wang M, Qian B, Ouyang L, Shi Y, et al. (2018) Aryl hydrocarbon receptor activated by benzo(a)pyrene promotes SMARCA6 expression in NSCLC. Am J Cancer Res 8: 1214-1227. [Ref.]
  17. Bauer AK, Umer M, Richardson VL, Cumpian AM, Harder AQ, et al. (2018) Requirement for MUC5AC in KRAS-dependent lung carcinogenesis. JCI Insight 3: e120941. [Ref.]
  18. Pathak GP, Shah R, Kennedy BE, Murphy JP, Clements D, et al. (2018) RTN4 knockdown dysregulates the AKT pathway, destabilises the cytoskeleton, and enhances paclitaxel-induced cytotoxicity in cancers. Mol Ther 26: 2019-2033. [Ref.]
  19. Gantenbein N, Bernhart E, Anders I, Golob-Schwarzi N, Krassnig S, et al. (2018) Influence of eukaryotic translation initiation factor 6 on non-small cell lung cancer development and progression. Eur J Cancer 101: 165-180. [Ref.]
  20. Fang C, Li XP, Chen YX, Wu NY, Yin JY, et al. (2018) Functional miRNA variants affect lung cancer susceptibility and platinum-based chemotherapy response. J Thorac Dis 10: 3329-3340. [Ref.]

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Article Information

Article Type: MINI REVIEW

Citation: Agius LM (2018) The Initial Emergence Phenomenon in Patterned Carcinogenesis in Lung Neoplasia. Int J Cancer Res Mol Mech 4(1): dx.doi. org/10.16966/2381-3318.140

Copyright: © 2018 Agius LM. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Publication history: 

  • Received date: 07 Sep, 2017

  • Accepted date: 06 Oct, 2018

  • Published date: 12 Oct, 2018