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Insights of Cisplatin Resistance in Cervical Cancer: A Decision Making for Cellular Survival

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Elizabeth Mahapatra, Salini Das, Souvick Biswas, Archismaan Ghosh, Debomita Sengupta, Madhumita Roy and Sutapa Mukherjee

Submitted: 22 April 2021 Reviewed: 20 May 2021 Published: 03 August 2021

DOI: 10.5772/intechopen.98489

Cervical Cancer IntechOpen
Cervical Cancer A Global Public Health Treatise Edited by Rajamanickam Rajkumar

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Cervical Cancer - A Global Public Health Treatise

Edited by Rajamanickam Rajkumar

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Abstract

The clinical scenario of acquired cisplatin resistance is considered as a major impediment in cervical cancer treatment. Bulky drug-DNA adducts formed by cisplatin elicits DNA damage response (DDR) which either subsequently induces apoptosis in the cervical cancer cells or enables them to adapt with drug assault by invigorating pro-survival molecular cascades. When HPV infected cervical cancer cells encounter cisplatin, a complex molecular interaction between deregulated tumor suppressors, DNA damage-repair enzymes, and prosurvival molecules get initiated. Ambiguous molecular triggers allow cancer cells to cull apoptosis by opting for a survival fate. Overriding of the apoptotic cues by the pro-survival cues renders a cisplatin resistant phenotype in the tumor microenvironment. The present review undrapes the impact of deregulated signaling nexus formed due to crosstalk of the key molecules related to cell survival and apoptosis in orchestrating platinum resistance in cervical cancer.

Keywords

  • HPV
  • Cervical cancer
  • Cisplatin resistance
  • tumor suppressors
  • DNA-damage repair
  • prosurvival signaling

1. Introduction

Cervical cancer, one of the widespread gynecological cancers, accounts for the maximum deaths amongst women across the globe. As per GLOBOCAN 2018, cervical cancer is helmed as the fourth leading cause of mortality and morbidity in women after breast and ovarian cancers [1]. As revealed from the data collated by World Health Organization (WHO) in 2013, over 85% of the cervical cancer cases had surfaced mostly from developing countries with a poor socio-economic backdrop [2]. Women, owing to lack of awareness, often arrive for seeking medical help when the malignant growth of cervix has attained advancement [3].

Infections with a special class of oncogenic DNA viruses called Human Papilloma Viruses (HPVs), hailing from the viral family Papillomaviridae, are highly accredited for the malignant transformation of cervix. Principally, HPVs are sexually transmitted [4]. On the basis of its carcinogenic potentials, HPVs can be categorized as –(i) low-risk HPVs(lr-HPVs) like HPV 6, 11, 42, 43 and 44, and (ii) high-risk HPVs(hr-HPVs)like HPV 16, 18, 31, 33, 34, 35, 39, 45, 51, 52, 56, 58, 59, 66, 68 and 70 [4, 5]. Persistent and prevalent infections with hr-HPVs contribute in development of cervical cancer alongside other cancers such as the cancer of vagina, vulva, penis, anus, head and neck. HPV infections may also give rise to anogenital warts and recurrent respiratory papillomatosis [5, 6]. Besides HPVs, several other risk factors have been implicated in the etiology of cervical cancer. These mainly include long term use of oral contraceptive [7], smoking [8] and infections with Chlamydia trachomatis [9].

Cervical cancer progresses through stages of mild dysplasia, moderate dysplasia and severe dysplasia to finally aggravate into carcinoma in situ and invasive cancer stages [10]. The International Federation of Gynecology and Obstetrics (FIGO) classify these developmental grades of cervical intraepithelial neoplasia (CIN) into various stages [11, 12]. Rise in the global disease burden is majorly due to treatment failure and disease recurrence [13]. The advent of vaccination has allowed for pre-infection protection [14]. However, lack of cost-effectiveness has limited its use to only a certain section of the society, particularly in low income countries like India. The therapeutic modality therefore, is skewed to chemotherapy and radiotherapy. Stage specific treatment regime is followed for treating cervical cancer [15]. As per FIGO conventions, Stage IIB-IVA denotes invasive stages where treatment is ensued in forms of conventional modes of chemotherapy and radiotherapy [11]. Traditionally, chemotherapy involves use of platinum ligated drugs like cisplatin (cis-diamminedichloroplatinum; CDDP) [16, 17]. Cisplatin in combination with other chemotherapeutics is often employed for treating invasive stages [16]. Patients are often subjected to treatment with cisplatin as a ‘radiosensitizer’ prior to radiotherapeutic intervention in the Concurrent Chemoradiotherapy (CCRT) regime [16]. Accordingly, cisplatin is the ‘drug of choice’ to oncologists for treating cervical cancer irrespective of its different stages.

In the process of HPV mediated cervical carcinogenesis several molecular changes are incited which remodels the metabolic profiles of the cervix [18]. HPV induced metabolic paradigm shift bestows the cells with therapy evasive properties. Consequentially, neoplastic cells emerge as highly dynamic and evolving entities [19]. On encountering drugs, the rewired signaling cascades of the tumor cells residing in the cervix get triggered. These eventuate in increased metabolism of chemotherapeutics like cisplatin, finally catering in reduced intracellular drug accumulation [20], paving a way for acquired cisplatin resistance. This chapter majorly discusses the mechanisms underlying the acquirement of resistance towards cisplatin as a result of deregulated activities of tumor suppressors, DNA damage repair enzymes and prosurvival molecules, mediated due to HPV infections.

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2. HPVs: Integral to etiology of cervical cancer

HPVs are relatively small non-enveloped viruses with a diameter of 55 nm. It has a double stranded circular DNA genome which is 8 kb long and is enclosed within an icosahedral capsid composed of 72 capsomers [21, 22]. Functionally, the HPV genome is regionalized into-i) a non-coding regulatory region called the long control region (LCR) or the upper regulatory region (URR), ii) an early region which houses E1, E2, E4, E5, E6 and E7 genes, and (iii) a late region which is made up of late expressing genes such as L1 and L2 [23]. LCR regulates the process of viral DNA replication via controlling the transcription of Open Reading Frames (ORFs). The lately transcribed proteins L1 and L2 are the structural proteins of the viral capsid. The early genes are dictators of viral replication, transcription, assembly and oncogenesis. Particularly, E6 and E7 are oncogenic and they degrade the cell cycle regulators like p53 and pRb to eventuate in cervical carcinoma [23].

These miniscule infectious agents access the cervical epithelial layer through crevices or microabrasions that generally forms due to mechanical shock or injury. Following entry, HPVs integrate their genome with that of the host to initiate the process of malignant transformation of the cervix (Figure 1). The carcinogenesis of cervical epithelium begins with the onset of viral lifecycle which initiates with viral entry into basal cell layer of the epithelium [24]. The basal cell layer of the cervical epidermis enables multiplication and replication of the virus by providing them with a suitable microenvironment. Molecules expressed by the basal cells such as integrins (α6β1, α6β4), heparan sulphate, and proteoglycans are chemoattractants for HPVs [25, 26]. No sooner does the virus enter the basal cells the viral replication starts but owing to poor copy number the duplication of viral DNA becomes non-reproductive. However, as the infection load spreads into the parabasal and intermediate layers, which are majorly comprised of semi-differentiated cells or terminally differentiated keratinocytes, DNA copy number increases and productive viral replication commences [27]. Meanwhile, the process of cervical carcinogenesis gets driven as the virus multiplies and sustains itself in the host system.

Figure 1.

Host cell hijacking by HPVs. HPVs enter the cervical epithelium through micro abrasions to finally integrate its genome into the DNA of the basal cells to promote loss of genomic integrity. Carcinogenesis is accompanied by viral multiplication in the cervical epithelium.

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3. Concomitant molecular changes during cervical carcinogenesis upon HPV infection: an escape route to cisplatin therapy

3.1 Onslaught of HPVs deregulates tumor suppressors

HPV mediated neoplastic transformation of cervix kick starts with the abridgement of tumor suppressor functions. An array of experimentations conducted in in vitro and in vivo models have successfully established the immortalizing capacities of E6 and E7 viral gene products; ensued via degradation of cell cycle controllers like p53 and pRb [28, 29]. E6 promotes ubiquitin mediated degradation of p53 in assistance with E6-associated protein (E6AP), a homolog for MDM-2 expressed in cells infected with hr-HPVs [30, 31]. As per reports, E6AP very efficaciously reduces the half-life of p53 in HPV infected cervical carcinoma cells, precisely as MDM-2, the conventional p53 inhibitor [32]. The guardian of the genome, p53, controls and coordinates the major genetic players involved in cell cycle arrest [33]. On top of this, p53 choreographs DNA damage repair, and apoptotic events [34]. As the episome formation is successfully accomplished by the virus, DNA damage response (DDR) is triggered. Absence of functional p53 allows the cervical cells to skip G1-arrest [35]. These functions which are central to cell survival and death get violated in the HPV immortalized cervical cells owing to reduced p53 levels. A higher E6 level is inversely proportional to cellular p53 levels [36]. Contrarily, the oncoprotein E7 binds with hypophosphorylated retinoblastoma protein (pRb); releasing the growth promoter E2F from the Rb-E2F complex. E2F translocate to the nucleus to enable expression of genes that drive the infected cells through S-phase of the cell cycle [37]. Cumulative loss of function of both of these tumor suppressors enables the infected cells to progress through G1 and S phases even with genetic errors. Shortfall of repair processes ultimately paves a way for genomic disintegrity to prevail; mediating neoplastic growth. Recent reports suggest that E6 and E7 intervene into the tumor suppressor activity by recruiting methyl groups on their promoter region [38, 39]. These oncogenic viral proteins also methylate cyclinA1 promoter and deregulate cell cycle progression to mediate tumorigenesis [40].

3.2 Cisplatin insensitivity: a consequence of HPV driven deregulation of tumor suppressors

HPV immortalized cervical cancer cells, especially those at the invasive stages, are subjected to treatment with platinum-ligated drugs like cisplatin. Following its cellular entry, cisplatin transforms into a very strong electrophilic species by hydrolytic activation. Such an activated drug generates an electrophilic attack on cellular nucleophiles like DNA and results in formation of bulky drug-DNA adducts which are beyond repair [41]. Inevitably, cancer cells harboring complex cisplatin modified DNA will be arrested in the G1 phase of the cell cycle particularly; due to generation of DDR response and subsequent activation of p53. Generation of cisplatin-DNA adducts activates Ataxia Telangiectasia Mutated (ATM)vis a visATM- and Rad3-related (ATR) proteins; culminating into phosphorylation at serine 15 residue and stabilization of p53 [42]. ATR along with various other proteins form an axis of ATR/CHK2/p53/p21; which ultimately mediates apoptosis [43, 44, 45, 46]. Therefore, p53 functional status is central to mediation of cisplatin cytotoxicity. This was first demonstrated in a study conducted with small-cell lung cancer cells where adenoviral delivery of p53 sensitized them to cisplatin and resulted in apoptosis [47]. A similar study carried out with ovarian cancer cells, reflected cisplatin induced apoptotic death upon adenovirus mediated delivery of p53 [48]. This tumor suppressor takes up multi-modal routes to facilitate cisplatin-induced cell death. Specifically, p53 increases the susceptibility of cancer cells towards cisplatin by degrading FLIP (FLICE-like inhibitory protein) and by binding with the anti-apoptotic mediator Bcl-xl to inactivate its function [49, 50]. It further activates other tumor suppressors like phosphatase and tensin homolog (PTEN) to shut down PI3K/Akt pathway [51]. Sometimes, hyperinduction of p53 can disable AMP-kinase (AMPK) [52]; thereby forcing the cancer cells to succumb to cisplatin cytotoxicity.

In HPV infected cells, this entire p53 dictated cell-death inducing pathway is compromised owing to functional absence of the tumor suppressors. E6 mediated prior degradation of p53 in cervical cancer cells, unprecedentedly makes them tolerant to the drug. It has been experimentally demonstrated that p53-Bax signaling axis elicited cisplatin induced apoptosis in cervical cancer cells [53]. Even in multiple clinical studies, patients retaining wild-type p53 have been found to respond better to platinum based chemotherapy [54]. Expression patterns of p53 are predictive of success rate of cisplatin treatment in adeno-carcinoma of the uterine cervix [55]. A very recent report has envisaged the contribution of p53 in restoring cisplatin sensitivity in CDDP resistant cervical cancer cells, particularly during combination treatment with doxorubicin [56].

3.3 HPV mediated impairment of DNA repair machinery: an auto-corrector of cisplatin-DNA adducts in cervical cancer

Early genes E1 and E2 drive the process of viral replication in the host by acting as an origin recognition factor (ORF) and by imparting helicase [57]. Mostly, the viral replication is dependent upon host cell factors, especially those which are involved in DNA damage repair pathways [58]. Not only HPVs, but other viruses like hepatitis C virus (HCV), Epstein–Barr virus (EBV) and human cytomegalovirus (HCMV) concocts the components of DNA damage repair pathway to survive in the host cells [59, 60]. HPV, while attempting to integrate its genome into the host cell’s DNA, incurs DNA damage that eventually evokes DDR.

The host cell has various repair pathways working in a well-knitted fashion to clear off irrelevant mistakes that may arise during the process of DNA replication. Some of these include- base excision repair (BER), nucleotide excision repair (NER), mismatch repair (MMR), homologous recombination (HR) and non-homologous end joining (NHEJ). This machinery actively functions to correct errors incorporated in DNA during replication while the cell is gradually traversing through different stages of the cell cycle. In instances of assault to DNA architecture hurled as single strands or double strand breaks, recruitment of ATM or ATR proteins occur at the site of damage. Protein complex comprised of MRN (MRE11-RAD50-NBS1) and Tip60 recognizes and recruits these proteins to the site of damage. ATM phosphorylates a series of downstream effectors which includes CHK2 and the histone H2A (H2AX) to begin with the repair process. For correcting double strand breaks, ATM switches over to HR pathway wherein the process of repair is executed by breast cancer 1/2 (BRCA1, BRCA2), RAD51 and Partner and Localizer of BRCA2 (PALB2) molecules [61, 62, 63]. In all cases, p53 is found to be the sole dictator of the process as it allows repair to occur by arresting cells with erroneous DNA.

Cervical cancer cells infected with hr-HPVs exhibit an upregulation of ATM pathway. Throughout the viral lifecycle, ATM response is constitutively kept activated owing to phosphorylation of its downstream effectors namely CHK2, NBS1 and BRCA1 [62, 63]. Oncogenic early protein E7 along with higher levels of E1 keeps ATM activity always at a hike. E1, the ORF while imparting helicase action, forms pseudoviral replication origins which initiate the process of DDR by stalling replication forks [64, 65]. In high-risk HPV infected cervical cells, the candidates of ATM pathway accumulates in the nucleus [66]. The differentiated and undifferentiated cells of the cervical epithelium packed with viral genomes also exhibit an upregulation of homologous recombination factors [67, 68]. Studies with pharmacological inhibitors have further delineated that ATM remains activated all throughout the viral life-cycle. It aids in amplification of viral genome within the differentiated squamous cells [69].

In addition to ATM, HPVs also activate ATR pathway. In HPV infected cells considerably higher levels of ATR-interacting protein or ATRIP and DNA topoisomerase 2-binding protein 1 or TopBP1 were noted [70]. Multiple studies have shown that in cells infected with HPVs has remarkably higher levels of total and phosphorylated forms of ATR as well as its downstream effectors, CHK1 [70]. ATM and ATR pathways provide the virus with an access to the host replicative machinery. E7 destroys Rb along with other related tumor suppressors such as p107 and p130, comprising the family of pocket proteins to control the transit of the cells from G1 phase to S-phase. Moreover, the released E2F translocates to the nucleus and lead to translational activation of the responsive gene, some of which are candidates of DNA damage repair pathways [70].

3.4 HPV seized DNA repair machineries of cervical cancer cells encourages acquired Cisplatin resistance

Upregulated activities of DNA damage repair enzymes empower cervical cancer cells to quickly repair the cisplatin-DNA adducts. Cisplatin generates intrastrand cross-links in the DNA to primarily activate nucleotide excision repair (NER) system [71]. It has been proposed that NER prevents apoptosis in cisplatin treated cells via activation of the members of the ATM pathway followed by its recruitment to the site of damage in the DNA. In cervical cancer cells, already activated ATM, immediately starts chewing away drug-DNA adducts; leading to resistance. Over 20 proteins hailing from the excision repair cross-complementation group 1 (ERCC1) partake in this process of clearing away the cisplatin-DNA conjugates [72]. At the 5′ site of the bulky cisplatin-DNA lesions, ERCC1 gets co-recruited with ERCC4 for excising away DNA-adducts [73]. In HCA-1R, a cisplatin resistant cervical cancer cell line, an upregulation of ERCC1 expression is recognized. Poor cisplatin responders with locally advanced cervical squamous cell carcinoma exhibit elevated levels of ERCC1 [74]. ERCC1, therefore, is considered as a prognostic biomarker for assessing the survival rate of patients receiving chemotherapy or CCRT [75, 76]. Another evolutionarily conserved DNA repair pathway is Mismatch Repair (MMR) pathway which is highly implicated in cisplatin resistance of cervical cancer cells [77]. Amongst the MMR proteins, MutS homolog 2 (MSH2) has been identified as a contributor of cisplatin resistance in cervical cancer cells [78]. Post-meiotic segregation 2 (PMS2), another key member of the MMR system is found to be negatively correlated with cervical cisplatin resistance [79, 80, 81, 82].

3.5 HPV mediated upregulation of prosurvival signaling cascades: Another contributor of cisplatin resistance in cervical cancer

‘Abortive infection’ often referred to active HPV infection, induces the genesis of both benign and malignant neoplasms of the cervix [83]. The oncogenic viral early gene products initiates cervical carcinogenesis by interacting with the crucial prosurvival signaling cascades of the host cell [84]. Besides abrogating p53 and pRb functions, HPVs opportunistically modulate four important cellular survival pathways by interacting with their upstream effectors such as growth factor receptor, notch receptor, Ras along with phosphatidylinositol 3-kinase subunit C (PI3KCA) gene which is second messenger activating Akt kinases [85, 86].

3.5.1 Activation of PI3K/Akt signaling

PI3K, particularly was found to be amplified and overtly activated in HPV-induced cervical cancers [87, 88]. The activation of MAPK/ERK in turn alters transcription of multiple genes that are important for regulation of cell-cycle progression and cell proliferation. Thus, activation of PI3K begets in Akt activation via phosphorylation of the protein in most of the HPV infected cancers. HPV16 E6 activates receptor protein tyrosine kinases (RTKs) viz. epidermal growth factor receptor (EGFR), insulin receptor beta and insulin-like growth factor receptor beta; lying upstream of the PI3K/Akt pathway [89]. Activation of Akt results into a series of changes in downstream targets. Akt, furthermore can phosphorylate E6 to promote its ability to interact with 14–3-3σ, an important protein required for carcinogenic progression [90]. A strong association between HPV and surged c-myc expression has been evidenced [91, 92, 93]. Reportedly, interaction between E6 and c-myc activates the enzymatic function of telomerase [94, 95]. In a clinical study, thirty nine out of 46 cervical cancer specimens evinced phosphorylation of Akt at serine 473 [96]. Akt activation was obtained in about, forty-eight percent of stage Ib2-IIb cervical cancer patients. HPV infection destabilizes the host genome for which mutations may be incurred in PIK3CA gene. Some mutations may be activator mutations accounting in Akt hyperactivation in cervical as well as many other HPV-induced cancers [95]. Oncogenic mutations and translational amplification of PIK3CA gene, switch on PI3K/Akt signaling invigoratingly; driving HPV mediated tumorigenesis.

3.5.2 Activation of mTOR signaling

mTOR kinase functions as a cellular rheostat that amalgamates cellular signaling pathways after sensing growth factor, starvation and energy status. Recently, it has been reported that Akt/mTOR activation occurs immediately after exposure to HPV16 pseudovirions [96]. mTOR activation is frequently observed in cervical squamous cell carcinoma, as well as in most HPV positive head and neck squamous cell carcinomas (HNSCC), and oropharyngeal cancers (OPSCC) [93, 97]. HPV oncoproteins E7 and E6 can chronologically activate AKT through pRb binding and subsequently stimulate mTOR in its complex 1 (mTORC1). These upregulated prosurvival signaling molecules lead to a shift in metabolic paradigm of the cancer cells. When subjected to cisplatin treatment, the HPV infected cervical cancer cells start to metabolize the drug faster than usual. This result in rapid drug efflux and eventually lessens intracellular cisplatin levels to orchestrate cisplatin resistance. Therefore, most cisplatin resistant cervical cancer cells are often characterized by the presence of greater levels of cisplatin efflux pumps [98, 99]. Of late, Li et al. showed in their study that in cisplatin resistant cervical cancer cells with upregulated PI3K/Akt pathway, espouses surged levels of Lysosome-associated protein transmembrane 4β-35 (LAPTM4B-35) which is another cisplatin exporter [100, 101].

3.5.3 Activation of the Wnt pathway

Nuclear accumulation of β-catenin due to activation of the canonical Wnt/β-Catenin pathway leads to transcriptional activation of a plethora of proliferative genes. This is highly characteristic to HPV16-positive invasive cancers as well as early dysplastic lesions [102, 103]. This phenomenon of nuclear accumulation of β-catenin positively correlates with progression of cervical cancer [104]. Accordingly, β-catenin was found in higher frequencies within the nucleus of cervical cancer cell line SiHa (bearing integrated HPV16) and HeLa (bearing integrated HPV18) [105]. Lichtig et al. proposed that HPV16 E6 could mechanistically activate Wnt/β-catenin pathway in a p53 independent fashion [106]. β-catenin signaling pathway exhibited a regulatory activity over acquired resistance to cisplatin via upregulation of Bcl-xl [107]. Cisplatin resistance got promoted in neoplasia due to shut down of GSK-3β owing to activation of Wnt/β-catenin signaling [108].

3.5.4 Activation of the Notch pathway

Cellular prosurvival juxtracrine signaling axis involving TGFβ/Notch1 is found to be exhilarated in invasive cervical cancer [109]. As the cervical lesions progressed from intraepithelial lesions III to microinvasive carcinoma, Notch1 translocated from the cytoplasm to the nucleus for ease of function [110]. HPV E6 has been identified as an activator of Notch protein in multiple cervical cancer cell lines [111]. Upregulated activities of notch protein induce stemness in cervical cancer cells, thereby enabling them to evade cisplatin driven cytotoxicity. Inhibition of Notch1was found to revert epithelial to mesenchymal transition (EMT); restoring cisplatin sensitivity [112].

3.5.5 Telomerase activation

Viral oncoprotein E6 escalates human telomerase activity by upregulating its catalytic subunit hTERT or telomerase reverse transcriptase [113, 114]. E6 on being aided by E6AP binds to the hTERT promoter region to increase its transcriptional activity [112]. NFX1–123, an mRNA interacting protein gets positively regulated by E6, to maintain higher telomerase expression [115]. E6 upon binding to hTERT protein increases telomerase activity via posttranscriptional modifications [116]. Telomerase reverse transcriptase was reported to promote cisplatin resistance by suppressing apoptosis.

Orchestration of HPV induced signaling nexus in promoting cisplatin resistance in cervical cancer is well depicted in Figure 2.

Figure 2.

Concomitant molecular changes induced by HPV contribute in cisplatin resistance in cervical cancer. The viral oncoproteins, particularly E6 and E7 deregulate the crucial molecules involved in cellular metabolism, cell cycle progression, DNA damage repair differentiation, survival, and apoptotic death. These changes provide the cervical cancer cells to evade cytotoxic cell death upon treatment with cisplatin; leading to acquirement of resistance.

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4. Perspective insights

As the virus hijacks the host system, it flips the molecular dynamics according to its own survival benefit. As discussed in this review, loss of function of tumor suppressors, magnified activities of DNA repair enzymes and constitutional activation prosurvival signaling cascades in the HPV infected cervix, make the situation precarious. The conundrum of drug resistance that arises as a result of these existent changes, stymies therapy. Tracking these prior change can aid in planning conventional therapeutic regimes. Thus, these molecules can act as valuable prognostic biomarker before administration of cisplatin based chemotherapy to cervical cancer patients.

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Acknowledgments

The authors are indebted to the Director, Chittaranjan National Cancer Institute, Kolkata for encouraging the idea of the manuscript. The authors are grateful to Ministry of Health & Family Welfare, Govt of India for financial support to undertake the research.

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Conflict of interest

Authors declare no conflict of interest.

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Written By

Elizabeth Mahapatra, Salini Das, Souvick Biswas, Archismaan Ghosh, Debomita Sengupta, Madhumita Roy and Sutapa Mukherjee

Submitted: 22 April 2021 Reviewed: 20 May 2021 Published: 03 August 2021

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution 3.0 License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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